Está en la página 1de 17

Anti-Infective Agents in Medicinal Chemistry, 2008, 7, 101-117

101

Development of Non-Nucleoside Reverse Transcriptase Inhibitors for AntiHIV Therapy


Christer Sahlberg* and Xiao-Xiong Zhou
Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden
Abstract: The NNRTIs play an important role in the present therapy against HIV/AIDS. This review discusses the basic principles in the development of NNRTIs for HIV therapy. It also summarizes the NNRTIs in clinical use and the major series of NNRTIs in development phases. The authors intend to provide an overview of the NNRTI research and to elucidate some important factors in directing the future in the field such as genetic barrier, QD dosing, safety profile and combination with other anti-HIV agents. Despite the enormous progress that has been achieved in the NNRTI field in the past two decades, the present clinical pipeline appears to be insufficient to tackle the huge medical need. The efforts of finding new NNRTIs are certainly much motivated and can be highly rewarding.

INTRODUCTION AIDS, caused by the HIV virus, is one of the worlds leading causes of death with a major medical and economic impact on society. The current combination therapy of three or more drugs is increasing the survival of HIV-infected patients by many years and provides an improved quality of life. The present therapies are mainly based on the inhibition of two key viral enzymes: HIV reverse transcriptase (RT) and HIV protease (PI) as well as the inhibition of viral fusion. Based on the chemical structures and the inhibitory mechanism, the RT inhibitors can be divided into nucleoside and nucleotide RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) which bind to an allosteric site of HIV-1 RT located about 10 away from the catalytic site. The NNRTIs play an important role in current anti-HIV therapy as a part of a successful combination therapy. Different aspects of NNRTIs have recently been reviewed such as; NNRTIs in general [1-7], specific NNRTIs [8-13], resistance issues [14,15], x-ray and binding of NNRTIs [16,17], clinical use of NNRTIs [18-21] and toxicity issues with NNRTIs [22-25]. The present review intends to provide an overview of the landscape of NNRTI research, to highlight some important principles and aspects in the development of NRTIs. The review is divided into three parts (i) HIV-1 RT and its inhibition (ii) NNRTIs in clinical use and (iii) NNRTIs in development. RT AND ITS INHIBITION HIV-1 RT HIV reverse transcriptase is a multi-functional enzyme which has the enzymatic activities of RNA-dependent DNA polymerase, DNA-dependent DNA polymerase and RNase H. All of the three functions are essential to complete the reverse transcription. The polymerase activity of the HIV RT
*Address correspondence to this author at the Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden; Tel: +46 8 54683100; Fax: +46 8 54683199; E-mail: christer.sahlberg@medivir.com

shares similar feature as most DNA polymerases, however, with a higher affinity to RNA as a template. Kinetic studies of the enzymatic reaction indicate that the DNA polymerization takes place in an ordered mechanism. The reaction is initiated by the binding of the primer, in most cases the tRNALys , to the free RT, which is followed by the template binding to the binary complex. Then NTP binds subsequently to the complex. The multiple components complex undergoes a conformational change which is rate-limiting in the polymerization, forming a tight binding complex that enables the nucleophilic attack by the 3-hydroxyl of the primer on the incoming phosphate of the dNTP [26-29]. The RNase H activity catalyzes the degradation of the template RNA in the RNA/DNA hybrid during the reverse transcription. Both endo- and exonuclease activities have been found with HIV RT. Two mechanisms of action have been observed with the RNase H activities in HIV RT, namely the polymerase-dependent and polymerase independent. The former hydrolyzes the RNA template upon the elongation of the DNA chain and the latter removes the residual primary RNA before the DNA strand transfer [30-32]. HIV-1 RT is a heterodimer, consisting of a p66 subunit with 560 amino acids and a p51 subunit with 440 amino acids. The 2 subunits form a stable dimer which is essential for the enzymatic activity. The overall structure of HIV-RT resembles a right hand as shown in Fig. 1 where the subdomains of p66 are designated as finger (residues 1-85), palm (residues 86-117 and 156-237) and thumb (residues 238-318) regions. Besides, there are other subdomains as RNase H (residues 427-560) and connection (residues 319-426). The conserved residues Asp185, Asp186 and Asp110 form the polymerase active site in the palm domain [33]. Although the p51 subunit shares the same sequence as the N-terminal of the p66 subunit, the p51 subunit adapts a spatial arrangement totally different from the p66 subunit and the p55 subunit has no catalytic function as the corresponding Asp residues are buried in the structure. It is believed that p51 plays a role in maintaining the overall structure of the RT. The p66 finger and thumb domains are rather flexible and the nucleic acid template and primer are bound in this cleft passing between
2008 Bentham Science Publishers Ltd.

1871-5214/08 $55.00+.00

102 Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2

Sahlberg and Zhou

Fig. (1). The overall structure of RT1 1 From coordinates kindly supplied by Prof. Torsten Unge, Department of Cell and Molecular Biology, Uppsala university

the fingers and in front of the thumb domain. When dNTP is bound to the complex, the fingers bend towards the palm forming a catalytic pocket [34.35]. Due to the essential role of the HIV RT in the viral replication, the inhibition of RT is regarded as one of the most attractive targets in the anti-HIV chemotherapy. Based on the structure and the mechanism, HIV RT inhibitors can be classified as two groups, nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs ) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). The NRTIs, not discussed in this review, are competitive inhibitors to dNTP and need to be transformed through a phosphorylation process to their corresponding nucleoside triphosphates or nucleotide diphosphates which then are incorporated into the growing viral DNA chain and subsequently to terminate the DNA elongation. They are normally active against both HIV-1 and HIV-2. The NNRTIs, on the other hand, are almost inactive on HIV-2, need no metabolic activation and they bind to the enzyme independently from dNTP and template/ primer with a non-competitive kinetics to dNTP and are uncompetitive to template/primer. Different aspects on the inhibition of HIV-1 RT with NNRTIs are discussed below. Inhibition of HIV RT by NNRTIs The enzyme kinetic studies of the NNRTI in complex with RT suggested an allosteric mechanism, which has been confirmed by several X-ray crystallography studies of the RT co-crystallized with different NNRTIs [33, 36-42]. All known NNRTIs bind to one specific pocket in p66 subunit, which is about 10 away from the catalytic site. The pocket is located in the palm subdomain and surrounded by several stranded -sheets [34]. The pocket is basically hydrophobic

in nature and lined with many aromatic and hydrophobic aliphatic residues as Leu100, Val106, Tyr181, Tyr188, Phe227, Trp 229, Leu234 and Tyr232. It contains also some hydrophilic residues, Lys101, Lys103, Ser105, Asp192 and Glu224 (Fig. 2). The NNRTI binding pocket (NNBP) exists only when an inhibitor is bound to the enzyme [38, 43]. Upon binding of an NNRTI to RT, the side chains of Tyr181 and Tyr188, originally pointing to the hydrophobic center of the pocket, are now pointing towards the direction of the catalytic site. This conformation change creates the NNBP and this pocket can accommodate a space of about 620-720 3 which is approximately more than twice of the volume occupied by most of the present NNRTIs [43]. The formation of the new pocket brings about the dislocation of -sheets where the catalytic Asp residues sit, leading to a position shift of around 2 for the catalytic residues [44]. The mouth for entering the pocket is flanked by Pro225 and Pro236 which are located on flexible chains. The flexibility is crucial for permitting the entrance of the NNRTI and subsequently closing the mouth after the entrance of the NNRTI. A probable solvent accessible area is located at the interface between p66 and p51 surrounded by Leu100, Lys101, Lys103 Val179 and Tyr181 from p66 and Glu1138 and Thr1139 from p51. The residues in the NNRTI binding pocket contribute at a varied degree to the affinity between the inhibitor and the enzyme. Some interactions are crucial and play an important role in a majority of the NNRTIs. The aromatic residues in RT, like, Tyr181, Tyr188 and Trp229, provide very important hydrophobic -interactions with -electron containing components of the inhibitors. The inhibitors are also possible

Development of Non-Nucleoside Reverse Transcriptase Inhibitors

Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2

103

Fig. (2). NNRTI pocket with inhibitor and relevant amino acid residues1 1 Data from reference [40]

to increase their affinity to the enzyme through van de Waals interactions with various positions in RT i.e. Leu100, Val106, Val179 and Leu234. Interactions with Lys101, Lys103 and Glu1138 represent the possibility of catching electrostatic interactions. Many NNRTIs form H-bonds with the enzyme through the side chain as well as backbone amides. Loss of some key interactions will significantly reduce the potency of the inhibitor. For example, Tyr181 plays an important role in interacting with many NNRTIs and the fact that HIV-2 RT has a isoleucine in the 181 position partly explains the reason that many NNRTIs are inactive to HIV2, although HIV-2 RT shares an similar overall folding as HIV-1 RT [45]. Three mechanism hypotheses for the inhibition of HIV-1 RT by NNRTIs have been suggested and none of them should be regarded as mutually exclusive. In fact, the nature of a particular inhibitor may dictate which mechanism is dominant. The first mechanism suggests a disposition of the catalytic Asp residues. It has been shown by kinetic studies that a NNRTI present in RT has a relatively small effect on the dNTP binding with an overall affinity reduction of around 10 fold. Meanwhile the affinity of the primer/template duplex to the enzyme is increased [26]. Hence, the major effect of the inhibition is believed from the blocking of the chemical step, which was confirmed by the analysis of the pre-steady state burst of the DNA polymerization [44]. The structural studies of the NNRTI bound enzyme clearly showed the disposition of the catalytic residue, which can partly explain the blockage or low efficiency of the nucleotide transfer reaction. The second mechanism suggests a hindrance of the cooperative motion of the thumb/finger subdomains. The binding of the NNRTI can also cause a long range distortion of the

RT structure. It was found that the p66 thumb subdomain is rotated by 40 relative to the finger domains compared to their relation in the NNRTI unbound enzyme. Associated with the hinge movement of the thumb, p66 connection and RNase H subdomains are also distorted from the normal position in unbound enzyme [36]. A dynamic study of RT suggested that the NNRTI binding not suppress the mobility of the finger, thumb and palm subdomains, but it will interfere with the global hinge-bending movement that controls the cooperative motion of the subdomains [46]. The last mechanism suggestion is rather speculative, addressing the effect the NNRTI binding has on the interaction between the two subunits p66 and p51. The change of the dissociation free energy of the RT heterodimer has been observed when binding with a NNRTI, which may has an impact on the modulating of the enzymatic function, since the heterodimeric structure is essential for the RT activity [47,48]. The inhibition of HIV-1 RT is regarded as one of the most attractive targets in the chemotherapy against HIV/AIDS due to its essential role in the viral replication and NNRTIs have been proven to be important components in HIV/AIDS combination therapy. Today three NNRTIs have been licensed for clinical use, namely nevirapine, efavirenz and delavirdine (Fig. 3) and many structural classes are being explored. NNRTIs IN CLINICAL USE Nevirapine Nevirapine (Viramune) was developed and launched by Boehringer Ingelheim for the treatment of HIV infection [49,50]. As the first NNRTI to be introduced into HIV treat-

104 Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2

Sahlberg and Zhou

N O HN H N O S O Nevirapine N H O N H Efavirenz O N N HN F3C Cl O

Delavirdine

Fig. (3). NNRTIs in clinical use

ment, it dramatically changed the strategy of HIV therapy. Nevirapine has since been widely used in the combination therapy for HIV/AIDS in various treatment regimens. Nevirapine is a relatively potent inhibitor of wt HIV-1 with an IC50 of 39 nM in CEM T-lymphoblastoid cells and 44 nM in macrophages, measured based on p24 antigen reduction [49]. The IC95 value in MT-4 cells is about 400 nM. The Ki value for wt HIV-1 in the RT enzyme assay is about 200 nM. As a selective inhibitor of the viral polymerase, nevirapine has low inhibitory effect on cellular polymerases and is noncytotoxic up to a very high concentration (CC50 = 321000 nM). The substance is basically inactive against HIV-2. Nevirapine shows a strong synergistic effect in combination with NRTIs, hence being widely used in the combination therapy with anti-HIV nucleoside analogs. For examples, in the plague assays the IC50 value for AZT is 10 nM, and for nevirapine 32 nM. In the combination experiment, 50 % inhibition was achieved with 0.3 nM AZT and 10nM nevirapine giving a combination index of 0.24, which indicates a strong synergistic effect [51]. Nevirapine SAR has been extensively studied. The dipyridodiazepinone structure is important for nevirapine. Changing either pyridine of the structure to pyrido[2,3b][1,4]benzodiazepinone (compound 1) or pyrido[2,3b][1,5]benzodiazepinone (compound 2) will reduce the activity [52]. Although maintaining sufficient antiviral activity, the benzo compounds have much lower water solubility than nevirapine and are more susceptible to metabolic Ndealkylation in the N-11 position, which may have a negative impact on their in vivo DMPK profiles compared to nevirapine. Though the diazepinthione modification (compound 3) is allowed and, in most cases, can enhance the antiviral potency, the thiones are generally regarded as less attractive for development due to observations that many thiolactams will be metabolized rapidly and that the they are often less water soluble. The substitution on the lactam nitrogen (N-5) is allowed when the 4-position is unsubstituted (compound 4). Increasing the size of the N-5 substituents will reduce the activity. The substitution on N-11 is crucial for potency (compound 5). Removal of the cyclopropyl group abolishes the activity. The best activities are seen with small liphophilic groups, such as ethyl, propyl and cyclopropyl. Increasing the size of the substituent or introducing hydrophilic group or electron-withdrawing group diminishes the potency. Substitution on either pyridine rings as in compounds 6 and 7 have been extensively explored. In general,

substituents in 2-position appear to have limited effect on the activity, whereas substitution in the 3-position is unfavored. The methyl substitution at 4-position results in good potency. However, the substitution at 7-, 8- or 9-position can affect the potency negatively. Some of the 5-alkylated lactams substituted at 2-position with heterocycles (compound 8) like pyrazol, pyridyl and thiazolyl give good potency, which confirms the great tolerability of the 2-position [53]. The structural studies of nevirapine and its interaction with RT has shed some light to the understanding of its SAR and provided the useful information for the further modification of the structure [38,43,54,55]. Nevirapine adopts a butterfly-like conformation which is commonly seen with many NNRTIs. The molecule is fold such that the angle of the two pyridine rings is about 120. Due to the electron delocalization, the amide bond moiety in the 7-membered ring adopts an almost planar conformation. The cyclopropyl substituent points up and away from the tricyclic system. One of the pyridine keeps a strong -stacking with Y181, Y188 and W229, while the other has interactions with K101, K103, V106, V179, Y318 and even possibly with the main chain atoms of H235 and P236. Nevirapine has a very favorable DMPK profile. The compound is quickly absorbed after oral dosing, and the absolute oral bioavailability reaches as high as >90% in human [56]. At the same time, the compound has a long half life about 25 hrs. When dosed at 200mg twice daily, it can reach a steady-state trough level of around 16 M which is around 300 fold of the EC50 in cell culture. The protein binding level of the compound in plasma is rather low compared to other NNRTIs with a value of 60%. Nevirapine is mainly metabolized by CYP3A4 like other lipophilic NNRTIs. The hydroxylated metabolites can further undergo glucuronidation before the excretion via urine. Interestingly, nevirapine is also a strong inducer of CYP3A4. After 2-4 weeks dosing, the CYP catalyzed metabolism is found to be enhanced 1.5 2 fold. Therefore, the early recommended dose for nevirapine was 200mg once daily for the first two week and subsequently enhanced to 200mg twice daily [57]. However, the recent 2NN study has shown that it is possible to dose nevirapine QD together with 2 NRTIs with the same antiretroviral efficacy as with the BID dose regimens thus simplifying the treatment and enhancing the patient compliance [58]. Nevirapine is a relatively safe drug although it is extremely important to follow-up the first 18 weeks of dosing to detect any life-threatening skin reactions such as Stevens

Development of Non-Nucleoside Reverse Transcriptase Inhibitors

Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2

105

O 4 3 2 N 1 HN 5 N 11 6 7 8 N 10 9 N HN

O HN

O HN

Nevirapine

3 O O HN

R N

R N

HN

R N N N N N R 4 O N 5 N

R N

Het

N R 8

Fig. (4). Nevirapine SAR.

Johnsons syndrome, toxic epidermal necrolysis and rash and also life-threatening hepatotoxicity that can occur with the use of nevirapine [59]. The very low genetic barrier seen with nevirapine has had a great impact on the clinical use of nevirapine and is a driving force in the search of new NNRTIs. It was noticed very early that the rate of resistance development was very fast upon monotherapy with nevirapine [60]. The present use of nevirapine is of course as a part of combination therapy and has recently been reviewed [8]. The resistance development is still an debated issue as nevirapine is used in Africa for the prevention of HIV from mothers to infants and in a recent publication these aspects have been discussed and it was concluded that resistance after single-dose nevirapine occurs more readily than previously thought [61]. Delavirdine Delavirdine (Rescriptor) was originally developed by Upjohn and launched by Pharmacia&Upjohn for the combination therapy against HIV infection [62]. The compound is now marketed by Pfizer. Delavirdine has a good activity against HIV-RT with a Ki about 0.2 M for the wild type enzyme. In the cell culture, the ED50 reaches low nanomolar level. Given the extremely low cytotoxicity ( > 100 M), the compound has a selective index over 10000. However, the substance loses substantially its potency against resistant strains with single mutations such Y181C, K103N. which are commonly seen

with NNRTI treatment, as well as P236L which is specific for delavirdine. SAR of delavirdine has been thoroughly studied [63-68]. Basically, the molecule can be regarded as three parts, i.e. a left aromatic part, a central piperazine and a right aromatic part (structure 9). In the central part, Y can be a carbonyl or a methylene group, with marginal effect on the activities. However, varying the length of the spacer Y will significantly decrease the inhibition of RT. The best activity is seen with a 1 atom spacer. The right hand pyridine structure is crucial for the potency. Replacing it with phenyl ring or substituted phenyl ring will abolish the activity. Similarly, pyrimidine replacement will also destroy the potency (structure 10). The isopropylamino substituent on the pyridine is important (compound 11), however, not essential. Smaller alkylamino displacement is tolerated. Many aromatic rings, including substituted phenyl, aromatic heterocycles and fused aromatics, were explored as the left hand aromatic part. Although several aromatic rings maintain good activities, such as thienyl, benzofuryl and naphthyl, indole rings in general have a superior antiviral potency and furthermore a reduced inhibitory effect to the cellular DNA polymerases. In particular, the indoles being connected through 2-position (compound 12). Various substitutions on indoles were evaluated, 5-substituted analog were selected due to its good metabolic stability and relatively good potency (compound 13). A large variation of substituents is allowed in the 5position; for example, halogen, alkoxy give a similar activity as the methylsulfonamido group. Alkylaminopiperidines were studied as an alternative to the central piperazine struc-

106 Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2

Sahlberg and Zhou

N N H N O S O N H O Delavirdine 9 N Ar Y HN N Ar O 10 Ar N N

X Z N

X X N N Ar O 11 12 X N R H N N O R 13 N R H N N O R

N HN H N O S O N H 14 O N

Fig. (5). Delavirdine SAR.

ture. While the potency against wild type RT is a bit lower than delavirdine, compound 14 is slightly more active against wild type HIV in cell cultures and substantially more active against mutant RT such as Y181C or P236L [69]. Delavirdine occupies the same NNRTI binding pocket as other NNRTIs however with a very different binding mode as delavirdine is bulkier than the other NNRTI with a volume of about 380 3 opposed to 230- 290 3 for the others. The compound has also an overall shape which differs dramatically from other NNRTIs. The complex between delavirdine and RT is stabilized in a unique way; when bond, delavirdine extends beyond the usual pocket and projects into the solvent [70]. A few hypothesis were suggested as for the entry of delavirdine into the NNRTI BP [33, 37]. The delavirdine binding pocket is connected to the solvent through a channel between well-ordered -sheets and a highly mobile flap, and the entry of delavirdine is by means of this channel. Delavirdine also interacts with regions of NNRTI BP inaccessible to other NNRTIs. For example, the piperazine ring positions very close to V106 and the indole ring forms a strong hydrophobic interaction with P236 with seven inter-ring atom distances being less than 3.6 . Besides, the carbonyl oxygen in the central spacer is H-bonded to the main chain of K103.

Delavirdine is well absorbed in vivo. In human it can generally reach over 50% absolute oral bioavailability and in some patients even over 85% [71]. Delavirdine has nonlinear pharmacokinetics, showing 2 compartments and a substantial individual variation [72]. Thus, delavirdine was initially developed with an original dosage of 100mg TID and due to the above reasons the recommended dosage was finally set at 400 mg TID. Following the absorption, delavirdine distributes across cell membranes with a steadystate volume of distribution of around 0.8 L/Kg. The compound has a high protein binding (98%). The plasma half life is about 7-21 hours. Delavirdine undergoes extensive Ndealkylation, forming N-deisopropyl delavirdine as the major metabolite [73]. The main enzyme responsible for the metabolism of delavirdine is CYP 3A4. Besides, CYP2D6, 2C9 and 2C19 are also important in the metabolism of delavirdine. Delavirdine is also an inhibitor of CYP3A4 [74] which could potentially enhance the plasma levels of certain PIs that are metabolized by CYPA4 when co-administered with delavirdine. The absorption of delavirdine is much affected by the gastric pH and its solubility can decrease 200 fold when pH is increased from pH 2 to pH 7.5. The most common adverse effect associated with delavirdine is different degrees of skin rash. Hepatic transa-

Development of Non-Nucleoside Reverse Transcriptase Inhibitors

Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2

107

minase activity elevation has been reported. [75]. Delavirdine treatment can develop resistance quite rapidly and the compound loses substantially the efficacy against mutant strains of HIV virus. With a relatively high and inconvenient dose regimens involving 400 mg/3 times a day, relatively low potency and an unfavorable resistance profile, the compound is not as widely clinically used as the other two launched NNRTIs. Efavirenz Efavirenz (Sustiva) was developed by DuPont and later by BMS for the treatment of HIV infection in combination with other anti-HIV agents [76]. The product was first approved by FDA in 1998 for use in the triple combinations as an alternative to protease inhibitors. Due to the high potency against wild type and some mutant strains, excellent PK profile, the compound is regarded as the leading prescribed NNRTI as a safe and efficacious component of early HAART regimens. Efavirenz is a highly potent inhibitor of HIV RT with a Ki of 2.9 nM against wild type enzyme and an ED50 of 1.5 nM in MT-4 cells. The compound is not cytotoxic and has a CC50 of about 80M which gives a selective index about 80000. Despite with certain loss, it maintains good activities against many single mutants commonly occurred in HIV therapy such as the L100I, K101E, V106A, V179D and Y181C with Ki values ranging 7-18 nM and ED50 values ranging 3-100 nM. However, it loses potency against double or triple mutants. For example, the ED50 values against K101D+K103N, L100I+K101D, K103N+Y181C and L100I+K103N were reported to be 1.5 M, 1.5 M, 0.4 M and 25 M, respectively [77]. Efavirenz was found as the result of the optimization work starting from the lead structure 15 [76]. The thiourea structure has a good activity against HIV-1 RT, however, due to the metabolic instability and the potential safety risk, it was replaced by the urea scaffold with 4,4-dialkyl substitution, which maintained good potency and stability as exemplified by structure 16. The N-3 methyl group has limited effect on the potency. The choice of the alkyl group in the 4position groups is important for rendering the potency as well as oral bioavailability. Compound 17 is highly potent in cell culture with an ED50 of 12 nM [78]. Interestingly, the stereochemistry is crucial for the antiviral activity. The compound with (R) configuration in the 4-position (compound 18) is basically inactive with an ED50 of 9.3 M, which could be explained by an unfavorable binding to RT. Replacing the dihydroquinazolinone scaffold with a benzoxazinone scaffold led to the a further enhancement of potency and the improvement of PK profile, cf. structure 19 [79]. The Rgroups in 19 were explored in combination with the substituent in 6-position. When R is a small alkyl groups, it often gives better activity. Halogen substitution on 6-position is superior to electron donating groups such as amino, mono or di-alkylamino, alkoxy, alkyl or phenyl groups. Multi substitution pattern on the benzene ring were also studied [80]. Introducing more halogens in 7 or 8-position (compound 20) is tolerable, though with about 10 fold reduction of activity. However, introducing halogen substitution on both 7 and 8 positions, forming a 6,7,8-trihalo compound, will totally

abolish the activity. Interestingly, on the other hand, the introduction of difluoro to the 5,6 position of the dihydroquinazoline scaffold resulted in compounds more potent on the K103N mutation exemplified by DPC 963 (Fig. 6) as described by Corbett et al [81]. Reduction of the acetylenic bond to a cis-olefin and keeping the 6-chloro substituent resulted in a compound named DPC 083 that has both a high antiviral activity and a promising PK profile such as lower protein binding than efavirenz and a long half lives when dosed orally to chimpanzees. DPC 083 went into clinical trials but the development of the compound has most likely been discontinued. Similar to most NNRTIs, efavirenz binds to RT through strong hydrophobic interactions [41, 82]. The cyclopropylpropynyl group points to a sub-pocket surrounded by aromatic side chains of Y181, Y188, W229 and F227, where the left pyridine ring of nevirapine binds. The benzoxazinone ring is situated between the side chains of L100 and V106 in a sandwich shape. The edge of the benzoxazinone has contact with the residues Y318 and V179. A prominent nonhydrophobic contact is the H-bonding formed between the NH in benzoxazinone and the main chain carbonyl oxygen of K101. The interaction of efavirenz with the mutant RT has been a subject of great interest and the structural information shed some light to the understanding of the mechanism of the efavirenz resistance. K103N is one of the major mutations efavirenz and other NNRTIs encounter. The structure of efavirenz with K103N mutant clearly shows that the mutation causes a significant conformational change within the binding pocket. The bigger asparagine side chain pushes efavirenz deeper into the pocket, which in turn forces the side chain of Y181 flip to opposite direction and its OH is displaced for more than 8 . This affects the position of E1138 and K101. The displacement of efavirenz itself is about 0.5 for the carbonyl oxygen and 0.7 for the cyclopropyl group, which is sufficient to alter some contacts between efavirenz and the enzyme. However, efavirenz loses the activity against single mutants much less than nevirapine in general. A hypothesis is forwarded from the structural study to explain the phenomenon. The overall size of efavirenz in relation to its binding size may determine its ability to adapt a mutation. A smaller inhibitor can reposition itself within the pocket whereas nevirapines bulky ring system remains relatively rigid and no such repositioning is possible [81]. The PK of efavirenz has been extensively studied. A study in rats and monkeys indicated a good oral bioavailabity of 16 and 42%, respectively and long half life especially in monkeys was observed [83]. The long half life is an important property which potentially enabling a QD regimen. Further studies have confirmed this and the clinical dose for efavirenz is 600 mg QD. The PK properties are fully described in the prescribing information for the drug [84]. Efavirenz is a highly lipophilic compound with a log P value > 4 and an aqueous solubility <20 g/ml. Efavirenz absorption is basically unaffected by food with normal fat content, whereas a high fat content meal can substantially increase the absorption. The compound binds extensively to plasma proteins with an unbound percentage as low as 0,5 % in human [83]. The main metabolites of efavirenz are from hydroxylation of the benzene ring and their glucuronates [85].

108 Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2

Sahlberg and Zhou

Cl 6 7

F3C 4 N H Efavirenz O O Cl N H 15

R1 OEt N S 16 N H Cl

R2 N O

R N Cl N H 17 Cl NH O N H 18 NH O N H 19 N Cl F3C O O

F3C Cl N H 20 O O F

F FC 3 NH N H DPC 963 O

F3C Cl N H NH O

DPC 083

Fig. (6). Efavirenz SAR.

The metabolism is primarily catalyzed by CYP3A4 and CYP2B6. At the same time, efavirenz has certain degree of inhibitory effect on CYP3A4, CYP2C9 and CYP2C19, which may lead to some drug-drug interaction. The metabolites are excreted through bile and urine, with less than 1% appearing as unchanged drug in urine [84]. The clinical efficacy of efavirenz is well documented for example in the 2NN study which involved 1216 treatment nave patients [58]. Treatment failure occurred in 151 patients (38%) of 400 assigned to efavirenz 600 mg QD in combination with stavudine and lamivudine which was somewhat less than the group receiving nevirapine QD or BID. There is a possibility that the efficacy of efavirenz is more sustainable than of nevirapine BID. The safety profile was better for efavirenz and more importantly the arm with both efavirenz and nevirapine gave most treatment failures and adverse effects showing that in contrast to NRTIs and PIs combinations of NNRTIs should be avoided. The advantage of using efavirenz in salvage therapy is not as well established. In a recent study the use of efavirenz as a HAART component was compared in treatment nave patients and patients with treatment failures from different PI-containing regimens was compared [86]. The result indicated clearly

that the efavirenz initial triple HAART therapy led to a better outcome than the use of efavirenz in the salvage group. This might be explained by the broad spread of viral resistant viruses and cross resistance over time. Actually, it was also somewhat surprising as it occurred in patients never taken NNRTI drugs. This observation seems to point to a relatively low genetic barrier of efavirenz, which also has been shown in several in vitro studies. The clinical use of efavirenz has recently been reviewed [10]. The major adverse reactions reported with the efavirenz treatment are CNS related, skin rash and liver and transaminase activity enhancement [84]. Skin rash is a common adverse effect for all NNRTIs whereas the CNS disturbances including nightmares are specific for efavirenz. These adverse effects together with a relatively low genetic barrier, make efavirenz not to be an ideal drug although efavirenz is currently the mostly prescribed NNRTI and is recommended for the first-line therapy. There is certainly room for new NNRTIs with properties such as high potency on wt virus and resistant virus, a high genetic barrier, DMPK properties enabling QD dosing and an improved safety profile. The next section will deal with new NNRTI compounds under development.

Development of Non-Nucleoside Reverse Transcriptase Inhibitors

Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2

109

NNRTIs IN DEVELOPMENT Nevirapine Analogs The low genetic barrier of nevirapine has initiated a search for compounds more active on resistant forms of HIV-1. Nevirapine analogs with an arylalkyl tail on the 3ring system were explored, leading to an enhancement of the potency against certain HIV-1 mutants. Compound 21 in Fig. 7 is an example of such a compound with a much improved potency on the K103N+Y181C double mutation. The compound with an un-oxidized sulfur has, not unexpectedly, a low metabolic stability and was not explored further [87]. In an another paper, BI scientists described a series of compounds with carboxylic acids in the end of the tail [88]. Compound 22 was high lightened as showing a good metabolic stability but the compound had problem to cope with the single mutations Y188L and V106A. Further development led to BILR 355, a compound with a N-oxide containing tail [89]. The compound has an excellent antiviral profile with IC50 values below 6 nM in culture against many mutants including K103N and Y181C and the 103+181 double mutation, However, the compound has only moderate activities against the single mutations Y188L and V106A and the double mutations K103N+V106A and Y181C+G190A. BILR 355 has a shift of about 2 fold upon addition of 50% human serum (HS) to the assay. The metabolic stability of the compound is substantially increased in rats when codosing with ritonavir indicating that the compound is metabolized by CYP3A4. BILR 355 is now in phase II clinical trials and needs to be co-dosed with ritonavir for achieving an acceptable AUC and half life.
O HN N S N N N 21 O N O N N N

pyrimidine (DAPY) series of compounds from Janssen/Tibotec, are described in a recent paper [90]. The historical background from TIBO to the present DAPY compounds is also nicely summarized in the paper. The structures of the three major DAPY compounds, TMC120, TMC125 and TMC278 are depicted in Fig. 8.
CN CN CN

O HN N N TMC120 (dapivirine) CN CN NH Br

N N NH2

NH

TMC125 (etravirine)

HN

N N

NH

TMC278 (rilpivirine)

Fig. (8). Diaryl pyrimidines (DAPY).

TMC120 TMC120 is now developed as a vaginal microbicide, despite promising clinical efficacy seen with TMC120 as an oral drug as reported 2001 [91]. Tibotec out-licensed 2004 the compound to the international society for microbiocide (IPM) to be used as a vaginal microbicide for preventing the HIV infection in females [92]. A recent publication described the delivery of TMC120 from silicone elastomer vaginal rings in amounts sufficient to inhibit the HIV-1 replication [93]. TMC125
22 O COOH

N O N N N N+ BILR-355 O-

Fig. (7). Nevirapine analogs.

Diaryl Pyrimidine Series (DAPY) The properties and multidisciplinary efforts leading to TMC278, which is the latest compound in the diaryl

The initial SAR and anti-HIV-1 activities for the DAPY compounds that led to TMC125 were first reported in a paper from 2001 [94]. TMC125 was the most potent compound in the series with an impressive cell culture efficacy both on wt and on resistant forms of HIV-1 with IC50 values below 7 nM for wt HIV-1 and HIV-1 virus with the mutations , L100I, K103N, Y181C, Y188L, L100I+K103N and K103N+Y181C. The binding properties of TMC125 and earlier compounds in RT were assessed by the studies on xray crystallography of the complexes between RT and inhibitors and molecular modeling [95]. Surprisingly, there was not possible to get any structural information from the complex of wt-RT and TMC125 as this complex resolved at about 7 but it was possible to get a good resolution of 2.9 on the K103N-RT and TMC125 complex. These com-

110 Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2

Sahlberg and Zhou

pounds bind in horseshoe fashion and a suggestion why TMC125 and analogs are still active on various resistant forms of HIV-1 was given. The DAPY compounds, being quite flexible, have according the authors 2 ways to overcome the usual negatively effect mutations have on the affinities of RT inhibitors in the NNRTI binding pocket (NNIBP) (i) by torsional flexibility (wiggling) in a given binding mode where the inhibitors can adapt numerous conformers enhancing the binding to mutant HIV-1 and (ii) there is a possibility of repositioning and reorientation (jiggling) of the compounds within the allosteric pocket. The original SAR work was followed up with a publication describing the antiviral efficacy for TMC125 in various mutants and also in comparison with nevirapine, delavirdine and efavirenz in different virus strains in MT4 and PBMC cells, in patient isolates with multiple mutations and in a range of HIV-1 subtypes. The metabolic stability and effect on addition of human proteins in the cell culture assays were also studied [96]. As previously discussed, TMC125 has a very good antiviral efficacy on HIV-1 and also some modest effect on HIV-2 with an IC50 of 3.5 M. In the NNRTI resistant strains (1081 samples with 10-fold IC50 change compared to wt for at least one of the clinically used NNRTIs) TMC125 inhibited 77% of the strains with an IC50 below 10 nM whereas the figure for efavirenz was only 23%. This clearly indicates that TMC125 can be useful in patients infected with NNRTI resistant virus. TMC125 has a good stability in human microsomes with 85% compound remaining after a 2 h incubation. Despite a very high proteinbinding of >99%, TMC125 showed no or a very little fold shift of efficacy in cell culture when different human proteins such as 1-acid glycoprotein (AAA), human serum albumin (HSA) and human serum (HS) were added. Nevirapine showed a similar pattern whereas efavirenz was negatively affected by a factor of 20 upon the addition of 50% HS. The genetic barrier, as an important property for a NNRTI, has recently been investigated in vitro for TMC125 [97]. The rate of resistance development i.e. breakthrough of mutants were studied by sequential passage experiments using 2 different approaches, a) a low multiplicity of infection (MOI) using increasing concentrations of the inhibitor or b) using virus with high MOI and fixed concentrations of the studied compounds. The studies were conducted both with wt and resistant virus. The results indicated that multiple mutations were needed to get resistant virus insensitive to TMC125 and the time to resistance was considerably longer than that for nevirapine and efavirenz. Furthermore, when using the high MOI and a fixed concentration of TMC125 of 1.0 M, no virus breakthrough occurred after the studied 30 days. The effect of 40 nM TMC125 was equivalent to 1.0 M efavirenz i.e 100% virus breakthrough at about day 10. The TMC125 selection experiments yielded known NNRTI mutations such as L10I, Y1811C, and G190E as well as novel ones like V179I and V179F. However, those in vitro selected mutations may not necessarily lead to same outcome in vivo. For example, capravirine gave V10A/F227L in vitro but studies in in vivo yielded mutations in positions 101, 108, 190 and/or 188. This observation is further illustrated by the fact that in vitro experiments with efavirenz give not the K103N mutation that is the main mutation seen in vivo.

The phase IIb trials of this compound are completed and several phase III studies are under way. A phase II study with TMC125 on protease-inhibitor (PI) nave patients with NNRTI resistant virus was discontinued due to inferiority to the PI containing controls and the reason for this is not clear for the moment [98]. According Tibotec, this study has no effect on the phase III registration studies for TMC125 which are substantially different from the discontinued study in terms of trial design, patient population, formulation and background regimen. Data from 3 short-term (7 days), phase IIa clinical studies, dosing 900 mg BID of TMC125 formulated in PEG 4000, have been published. In the first study, TMC125 replaced nevirapine or efavirenz components in a triple drug therapy consisting of NRTIs and 1 NNRTI. Sixteen male patients were included with an mean viral load of 4.2 log10 RNA copies/ml, among whom 81% were nevirapine experienced and 19% efavirenz experienced. The median decrease in viral load in the study was 0.89 log10 RNA copies/ml [99]. The second study compared the results from monotherapy with TMC125 in antiretroviral therapy (ART) nave patients with a 5-drug regimen containing zidovudine, lamivudine, abacavir, indinivair and nevirapine also in ART nave patients. Twelve patients with a median viral load of 4.2 log10 copies /ml received TMC125 and 11 patients with a median viral load of 4.8 log10 copies/ml received the 5drug regimen. The results indicated similar decrease of viral load for the 2 regimens i.e. at day seven the median viral load was 1.92 for the TMC125 regimen and 1.76 for the 5drug regimen [100]. In the third study, 19 ART nave patients received TMC125 in a double-blind placebo controlled phase IIa clinical trial. In the TMC125 group the mean decrease after 7 days was 1.99 compared to 0.06 for the placebo group [101]. All these 3 clinical studies indicate that TMC125 dosed 900 mg twice a day has a good anti-HIV effect. TMC278 As previously mentioned, the multidisciplinary efforts leading to TMC278 is described [90]. The SAR and synthesis of this compound and other related compounds are described in another paper [102]. TMC278 has a very high potency in the cell culture system studied with IC50 below 8 nM for all mutants tested including the double mutants K103N+Y181C and L100I+K103N. The compound is relatively easy to prepare in 8 steps but has a risk of isomerization of the E-form to the Z-isomer in day-light and in a weak acid solution. The rationale behind the series was to utilize the interactions with the conserved W229 region. The most potent structures found were , -unsaturated nitriles which finally led to TMC278. The choice of this compound as the clinical candidate is somewhat surprisingly as it contains a potentially risky position which can react with various types of nucleophiles. This might be reflected by the relatively low non-toxic effect dose (NOEL) of 5 mg/kg reported for safety studies in dogs [90]. The compound is in phase IIb clinical studies and the outcome of a short study with TMC278 is recently published [103]. The study was a double-blind placebo controlled 7 day study using once daily dosing of 25, 50, 100 or 250 mg TMC278 to 47 ART nave HIV infected patients. The results showed, independent of the dose, a median drop of viral load

Development of Non-Nucleoside Reverse Transcriptase Inhibitors

Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2

111

in the TMC278 treated group of about 1.2 log10 copies/ml compared to 0.002 log10 copies /ml gained in the placebo group. The plasma concentrations in all subjects were, at all time points and for all doses, exceeding the targeted concentration of 13.5 ng/ml. Imidazoles Capravirine (S-1153), see Fig. 9, was originally developed by Shionogi, but later licensed and further developed by Agouron/Pfizer. Antiviral key-data of capravirine on wt HIV-1 and various mutant forms of HIV-1 has been reported [104]. The compound has IC50 values below 2 ng/ml against wt HIV-1 on various strains and in different cells and IC50 values ranging 0.3 to 7 ng/ml for many mutants including Y181C and K103N in MT-4 cells. Furthermore, S-1153 has IC50 values below 10 ng/ml for various clinical isolates and is considerably more potent than AZT on these isolates. The compound shows a substantially slower rate of resistance development than nevirapine when passaged in an in vitro system. It took more than 9 passages to generate resistant virus (IC50 =740 ng/ml) with the double mutation V106A+F227L compared to 2-3 passages for nevirapine. Phase I clinical studies started in 1997 and some clinical data have been published [105]. The results indicate a good antiHIV-1 effect when dosing 25 mg/kg three times a day (TID) with a decrease of HIV-1 viral load with 1.34 log10 copies/mL. The compound has a relatively short half life in humans which has been further determined to be about 1.8 h upon a single dose of 1400 mg. The half life is increased to 8.3 h when co-dosed with ritonavir. The compound is extensively metabolized according to a very complicated metabolic pattern [106]. The compound was in phase II/III clinical studies for many years and the development finally discontinued as the combination therapy with capravirine as a component could not show a better effect than the standard triple drug regimens [107].
N O Cl S N O N Cl Capravirine (S-1153) NH2

Gilead has filed an extensive patent on various NNRTIs linked phosphonates in order to make NNRTI prodrugs and thereby potentially enhance the half-life of the parent compound [108]. One of the specifically claimed compound was the prodrug of capravirine (23), depicted in Fig. 9. However, no biological data supporting a longer half-life in vivo was given in the patent. The Rega institute has patented various imidazoles related to capravirine [109]. One example of a specifically claimed compound is structure 24 in Fig. 9 with a modest IC50 value of 0.2 g/ml in MT-4 cells. Benzophenones Chan et al reported a group of highly potent benzophenone derivatives active both on wt virus and various HIV-1 mutants [110]. The compounds, GW4511, GW4751 and GW3011, cf. Fig. 10, showed excellent effect on wt and 16 different single and double mutations, with IC50 values below or equal 2 nM for wt virus and less that 10 nM for mutant virus including the clinically important Y181C and K103N mutations. The work was followed up with a successful SAR work leading to the clinical candidate GW678248 which has excellent anti-HIV-1 effect with IC50 values of 0.5 nM on wt virus, 1 nM on the K103N mutant and 0.7 nM on Y181C mutant in cell culture systems using MT4 cells [111]. A prodrug, GW695634, was made in order to increase the solubility and thereby the oral availability of GW678248 (Fig. 10). This prodrug was selected for clinical studies. The antiviral properties, protein binding shift and cytotoxicity of GW678248 were further studied and reported by Boone et al [112]. The excellent antiviral effect was confirmed and compared with nevirapine and efavirenz. The only mutants that gave IC50 values above 21 nM were single Y188L and triple V106I, E1138K and P236L which was formed from serial passages of wt virus. The compound has a protein binding shift of about 7 and a favorable selective index of over 2500 when comparing the cytotoxic effect with the antiviral effect on wt, Y181C and K103N HIV-1. Phase IIb studies with GW695634 showed good antiviral effect when dosed 100, 200, 300 or 400 mg BID as monotherapy [113]. However, the development of the compound has been discontinued due to safety issues related to rash and liver metabolic enzymes [6]. PETT Series

N O Cl S N O N Cl 23 Cl N H P O O O

Cl

HN N N

Fig. (9). Imidazoles.

24

The phenyl ethyl thiourea thiazole (PETT) series of NNRTIs originating from a collaboration between Medivir and Lilly which resulted in the clinical candidate trovidine with a IC50 value of 20 nM on wt HIV-1 when tested in MT4 cells [114]. Fig. 11 shows the structures of some representative PETT compounds. The emerging of the NNRTI resistance issues resulted in search for compounds active on resistant forms of HIV-1. The introduction of conformationally restricted cyclopropanes in the PETT series was beneficial for the activity on resistant forms of HIV-1 and the change to urea compounds was also beneficial for lowering the relatively high protein binding shift seen in cell culture with the thiourea compounds. The stereochemistry was also studied as well as extensive X-ray studies of the complexes between the inhibitors and both wt and resistant HIV-1. This work

112 Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2

Sahlberg and Zhou

H N O R O O O R1 Cl O S NH2 F F3C

H N O O O O O O Cl GW3011 S NH2

R=CF3, R1=F ; GW4511R=H, R1=CN; GW4751

H N O NC O O O Cl Cl GW678248 O S NH2 Cl NC

H N O O O O Cl GW695634 O S N H O

Fig. (10). Benzophenones.

resulted in MIV-150 and analogous compounds [40]. The interaction between wt- RT and MIV-150 is very well characterized as shown in Fig. 12. Very important is the internal hydrogen bonding net-work giving a derivative with optimal configuration to be bound to the enzyme. Interestingly, the two cis-enantiomers have similar potency which can be nicely explained by x-ray studies. A separate x-ray study with MSC-194, cf. Fig. 11, efavirenz and PNU14721 (a NNTRI from Pharmacia-Upjohn) on K103N mutant enzyme in comparison with wt structure of efavirenz showed that the K103N substitution gave no major changes in the positioning of the inhibitors in the NNIBP. It was concluded that the inhibitors bind in a conservative mode to K103N mutant and that the changes in affinity was attributed to changes in the chemical environment close to the mutated 103 position [41].

MIV-150 was taken into clinical studies by Chiron and an optimized the process route was recently published [115]. Due to the relatively low oral availability, MIV-150 is now being developed as an vaginal microbicide by the Population Council [116]. The focus on the K103N mutation resulted in the compound MIV-160 (Fig. 11) described in a patent [117]. The IC50 values, when tested in Medivirs cell culture system on wt and K103N, were 2 and 24 nM, respectively. MIV-160 was also tested at Virco and the IC50 values for wt and K103N were 0.3 and 0.7 nM, respectively, showing the well known fact that it is very important to compare compounds in the same assay. MIV-160 has a fold decrease of about 5 on the addition of 40% HS to the cell culture assay. In contrast to MIV-150 and analogs, it is only the (-)-enantiomer of
F O N H N H N CN

S N N H Trovirdine N H N

Br OH O

MIV-150

O N H OH

S N H N

CN

F O H H H N H O N H N CN

F O MSC-194

Fig. (11). PETT series (Medivir).

MIV-160

Development of Non-Nucleoside Reverse Transcriptase Inhibitors

Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2

113

Interactions with Glu1138? EWG, preferably slightly bigger Provides angle

Pi-stacking withTyr181, 188 F O H-bonding to Lys101 backbone

N Close-packingwith Trp229 OH H N

NH H-bonding network

Pi-interaction with Phe227 N

EWG, interaction with the "edge" of Phe227

Fig. (12). Interactions MIV-150 and wt HIV-1 RT.

the two possible endo (cis) tricyclic compounds that is bearing the anti-HIV activity. Uckun and co-workers have further explored the noncyclopropyl thiourea compounds and were able to patent some limited analogs whereof compound 25 in Fig. 13 was reported as the most potent one with a subnanomolar potency on wt HIV-1 in a cell culture assay using PBMC cells [118]. Some other compounds reported by Parker Hughes are also shown in Fig. 13. They extended the known positive effect of a methyl group in the benzylic position [114] and studied the stereochemistry of alkyl substitution at this benzylic position [119]. The results indicate that R-stereochemistry is optimal as exemplified for compound 26 in Fig. 13 which is about 10 times as active as the S-enantiomer.
S N N H 25 O S N H PHI-236 N H N Br N H N Br S N H 26 N H N Br

Pyrimidindiones HEPT was along with TIBO the first reported NNRTI. It has its origin from the NRTIs and has a modest IC50 value of 5 M on wt HIV-1 [121]. Optimization of the HEPT original structure led to MKC-442 which also is named emivirine (Fig. 14). The compound has an IC50 of about 15 nM against wt virus in MT4 cells [122]. The safety and pharmacokinetics of the compound have been reported [123]. Emivirine was licensed to Triangle Pharmaceuticals and entered clinical trials but returned back to Mitsubishi in 2004 when it had reached phase II. The present status of the compound is unknown. SJ-3366 is another HEPT related compound, discovered and developed by Sam Jin Pharmaceuticals. The structure is shown in Fig. 14. The anti-viral characteristics of this compound has been described [124]. The compound has a dual effect on HIV. Besides being a allosteric inhibitor of RT, it also inhibits the entry of the HIV virus into the target cells. Hence, on the contrary to most NNRTIs, the compound is also active on HIV-2 with an IC50 value of 170 nM in a CEM-SS cell system. The compound has high potency in a range of HIV-1 isolates and cells with IC50 values between 0.9 and 10 nM. The addition of serum proteins gave basically no effect on the potency of the compound except for the addition of HSA+ AAA which caused a protein binding shift of 10. The major drawback with the compound seems to be the very low potency on K103N and Y188C mutant virus and an unoptimal effect on Y181C resistant virus with the fold resistance of >83, 33 and 5, respectively. SJ-3366 was recently out-licensed to ImQuest Pharmaceuticals and is renamed IQP-0410 [125]. An IND application was expected to be filed 2006 according the homepage of the company.

Fig. (13). PETT series (Parker Hughes Institute).

Interestingly, another PETT derivative i.e compound PHI-236 in Fig. 13, was recently reported to have good effect in preventing HIV infection when used vaginally in a mouse model [120]. This further provides an extra support to the on-going clinical studies with MIV-150 and TMC120 as vaginal microbicides against HIV transfection.

114 Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2

Sahlberg and Zhou

O HN O O HO HEPT N S O O HN

MKC-442 (Emivirine) O

same scaffold although somewhat more advanced and decorated leading to compounds with increased potency on mutant forms of HIV-1 and especially on the Y188L mutation. This series of compounds is exemplified with compound 29 which shows only 4 fold loss on Y188L. This mutant causes much more problems to these triazole types of compounds than the K103+Y181C double mutation [128]. The series were originally developed by Valeant and one compound from the series was likely chosen as a clinical candidate (AR-806). Late 2006 this compound was acquired by Ardea biosciences and a phase I study is planned for Q2 2007 [129]. CONCLUSIONS The use of NNRTIs as an important part of successful combination therapy in HIV/AIDS patients have been well established and widely accepted. The drugs in clinical use, nevirapine, delavirdine and efavirenz, are relatively old and have their drawbacks. Nevirapine has a very low genetic barrier and certain adverse effects associated with liver toxicity; delavirdine has also a low genetic barrier in addition to its unfavored TID dosing and efavirenz an insufficient genetic barrier and frequent CNS side effects. All three compounds have problems with different degrees of skin rash. Nevirapine and efavirenz have PK properties such as they can be dosed once daily which is an important property for a HIV/AIDS drug to be competitive. However, the draw-backs with the existing compounds create of course a great need for new NNRTI drugs. Although the enormous progress that has been made in the NNRTI field in recent years, especially in terms of the antiviral potency, the NNRTI clinical pipeline seems not to be that impressive as hoped. The only compounds remaining in phase II/III trials seem to be the TMC125 and TMC278 from Tibotec. These compounds have excellent potency on HIV-1 and mutants thereof and probably a high genetic barrier which will cause a slow resistance development. Also to be successful the compounds need to have satisfactory safety properties and very importantly to be dosed once daily (QD). This pharmacokinetic property is not obvious for TMC125 but it seems that TMC278 can be dosed once daily. Regarding safety issues, TMC278 contains a potential reactive component that could jeopardize its further development. The need for new NNRTIs to be combined with other drugs, NRTis and/or PIs is still high. Reviewing the experiences from the NNRTI development and the clinical results, it point to several key properties an successful NNRTI may need to have, namely excellent potency on wt virus and clinically important mutations, high genetic barrier for resistance development, QD dosing, minimum adverse effect, good combination with other anti-HIV agents like NRTIs, PIs or fusion inhibitors and satisfactory DMPK and safety profiles are much motivated and can be highly rewarding. Time will show if any of the compounds described in this review will fulfill these criteria.

O HN HN HN O N O N F F

SJ-3366

27

Fig. (14). Pyrimidindiones.

Compound 27 in Fig. 14 was designed by the aid of molecular modeling, and is a conformationally restricted NHDABO derivative that was recently published by Italian scientists. The compound has a modest IC50 on wt virus of 30 nM and shows certain inhibitory effect (IC50 =160 nM) on the nevirapine mutant, Y181C [126]. Triazoles In 2006 two groups reported independently, about new series of NNRTIs using a triazole as the scaffold. In the first paper, compound 28 in Fig. 15 and analogs thereof were described [127]. This compound is one of the most active compounds in this sulfanyltriazoles series and shows single digit nM potent on wt HIV-1 and a relatively low decrease (24 fold) on the double mutant K103N+Y181C. However, it loses potency heavily against the Y188L single mutant (3500 fold). A second publication deals with compounds with the
N N N H N S O 28 NO2

N F3C N

N H N S N O

Cl

SO2NH2

ACKNOWLEDGEMENTS
29

Fig. (15). Triazoles.

The authors would like to thank Katarina Jansson for making the Figures 1 and 2.

Development of Non-Nucleoside Reverse Transcriptase Inhibitors

Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2 [39]

115

REFERENCES
[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Gulick, R.M. Clin. Microbiol. Infect., 2003, 9, 186. Goette, M.; Wainberg, M.A. In Viral Infections and Treatment; Rubsamen-Waigmann, Ed.; Marcel Decker: New York, 2003, Vol. 30, pp. 505-521. De Clercq, E. Chem. Biodivers., 2004, 1, 44. Balzarini, J. Curr. Top. Med. Chem., 2004, 4, 921. Tarby, C.M. Curr. Top. Med. Chem., 2004, 4, 1045. Boone, L.R. Curr. Opin. Investig. Drugs, 2006, 7, 128. Basavapathruni, A.; Anderson, K.S. Curr. Pharmaceut. Des., 2006, 12, 1857. For reviews on the clinical use of nevirapine, see: (a) Lange, J. M.A. JAIDS, 2003, 34, S40.; (b) Harris, M. JAIDS, 2003, 34, S53. For a review on capravirine, see: Sorbera, L.A.; Castaner, J.; Bayes, M. Drugs Future,2003, 28, 1149. For a review on clinical use of efavirenz, see: Fortin, C.; Joly, V. Expert Rev. Anti-infect. Ther., 2004, 2, 671. For a review on etravirine (TMC125), see: Davies, S.L.; Castaner, J.; Silvestre, J.S.; Bayes, M. Drugs Future, 2005, 30, 462. For a review on indolyl aryl sulfones (IASs), see: Silvestri, R.; Artico, M. Curr. Pharmaceut. Design, 2005, 11, 3779. For a review on the tight binding of PETT, HEPT and DABObased NNRTIs, see: DCruz, O.J.; Uckun, F.M. J. Enzym. Inhib. Med. Chem., 2006, 21, 329. Wainberg, M.A. JAIDS, 2003, 34, S2. Martinez, J.; Coplan, P.; Wainberg, M.A. Antivir. Res., 2006, 71, 343. Sluis-Cremer, N.; Temiz, N.A.; Bahar, I. Curr. HIV Res., 2004, 2, 323. Das, K.; Lewi, P.J.; Hughes, S.H.; Arnold, E. Progr. Biophys. Mol. Biol., 2005, 88, 209. Zhang, Z.; Hamatake, R.; Hong, Z. Antivir. Chem. Chemother., 2004, 15, 121. Quirk, E.; McLeod, H.; Powderly, W. Clin. Infect. Dis., 2004, 39, 98. Kappelhoff, B.S.; Huitema, A.D.; Beijnen, J.H. Drugs R., 2005, 6, 61. For reviews on the use of NNRTIs in vaginal microbicides, see: (a) DCruz, O. J.; Uckun, F.M. J. Antimicrob. Chemother., 2006, 57, 411.; (b) . DCruz, O.J.; Uckun, F.M. Curr. HIV Res., 2006, 4, 329. Kontorinis, N.; Dietrich, D. Semin. Liver Dis., 2003, 23, 173. Dietrich, D.T.; Robinson, P.A.; Love, J.; Stern, J.O. Clin. Infect. Dis., 2004, 38, S80. Abrescia, N.; DAbbraccio, M.; Figoni, M.; Busto, A.; Maddaloni, A.; DeMarco, M. Curr. Pharmaceut. Design, 2005, 11, 3697. Nolan, D. Drug Safety, 2005, 28, 1069. Rittinger, K.; Divita, G.; Goody, R.S. Proc. Natl. Acad. Sci. USA, 1995, 92, 8046. Majumdar, C.; Abbotts, J.; Broder, S.; Wilson, S.H. J. Biol. Chem., 1988, 263, 15657. Kati, W.M.; Johnson, K.A.; Jerva, L.F.; Anderson, K.S. J. Biol. Chem., 1992, 267, 25988. Hsieh, J.C.; Zinnen, S.; Modrich, P. J. Biol. Chem., 1993, 268, 24607. Schatz, O.; Mous, J.; Legrice, S.F. EMBO J., 1990, 9, 1171. Furine, E.S.; Reardon, J.E. J. Biol. Chem., 1991, 266, 406. Peliska, J.A.; Benkovic, S.J. Science, 1992, 258, 1112. Kohlstaedt, L.A.; Wang, J.; Friedman, J.M.; Rice, P.A.; Steitz, T.A. Science, 1992, 256, 1783. Jacobo-Molina, A.; Ding, J.; Nanni, R.G.; Clarck; A.D.; Lu, X.; Tantillo, C.; Williams, R.I.; Kame, G:, Ferris, A.L.; Clarck, P.; Hitzi, A.; Hughes, S.H.; Arnold, E. Proc. Natl. Acad. Sci. USA, 1993, 90, 6320. Huang, H.; Chopra, R.; Verdine, G.L.; Harrison, S.C. Science, 1998, 282, 1669. Ding, J.; Das, K.; Moereels, H.; Koymans, L.; Andries, K.; Janssen, P.; Hughes, S.H.; Arnold, E. Nat. Struct. Biol., 1995, 2, 407. Ding, J.; Das, K.; Tanillo, C.; Zhang, W.; Clark, A.D.; Jessen, S.; Lu, X.; Hsiou, Y.; Jacobo-Molina, A.; Andries, K.; Pauwel, R.; Moereels, H.; Koymans, L.; Janssen, P.; Smith, R.H.; Kroeger, K.M.; Micheida, C.J.; Hughes, S.H.; Arnold, E. Structure, 1995, 3, 365. Ren, J.; Esnouf, R.; Garman, E.; Somers, D.; Ross, C.; Kirby, I.; Keeling, J.; Darby, G.; Jones, Y.; Stuart, D.; Stammers, D. Nat. Struct. Biol., 1995, 2, 293.

[40]

[41] [42] [43] [44] [45] [46] [47] [48] [49]

[14] [15] [16] [17] [18] [19] [20] [21]

[50]

[51] [52]

[53]

[22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34]

[54] [55] [56]

[57] [58]

[58] [60] [61] [62]

[35] [36] [37]

[63] [64]

[38]

Hopkins; A.L.; Ren, J.; Esnou, R.M.; Willcox, B.E.; Jones, E.Y.; Ross, C.; Miyasaka, T.; Walker, R.T.; Tanaka, H.; Stammers, D.; Stuart, D.L. J. Med. Chem., 1996, 39, 1589. Hgberg, M.; Sahlberg, C.; Engelhardt, P.; Noren, R.; Kangasmets, J.; Johansson, N.-G.; berg, B.; Vrang, L.; Zhang, H.; Sahlberg, B.-L.; Unge, T.; Lwgren, S.; Fridborg, K.; Bckbro, K. J. Med. Chem., 1999, 42, 4150. Lindberg, J.; Sigurdsson, S.; Lwgren, S.; Andersson, H. Sahlberg, C.; Noren, R.; Fridborg, K.; Zhang, H.; Unge, T. Eur. J. Biochem., 2002, 269, 1670. Ren, J.; Nichols, C.; Bird, L.E.; Fujiwara, T.; Sugimoto, H.; Stuart, D.; Stammers, D. J. Mol. Biol., 2001, 312, 795. Esnouf, R.; Ren, J.; Ross, C.; Jones, Y.; Stammers, D.; Stuart, D. Nat. Struct. Biol., 1995, 2, 303. Spence, R.A.; Kati, W.A.; Anderson, K.S.; Johnson, K.A. Science, 1995, 267, 988. Ren, J.; Bird, L.E.; Chamberlain, P.P.; Stewart-Jones, G.B.; Stammers, D. Proc. Natl. Acad. Sci. USA, 2002, 99, 14410. Temiz, N.; Bahar, I. Proteins, 2002, 49, 61. Tachedjian, G.; Orlova, M.; Sarafianos, S.; Arnold, E.; Goff, S. Proc. Natl. Acad. Sci. USA, 2001, 98, 7188. Sluis-Cremer, N.; Arion, D.; Parniak, M.A. Mol. Pharmacol., 2002, 62, 398. Merluzzi, V.; Hargrave, M.; Labadia, K.; Grozinger, M.; Skoog, J.; Wu, C.K.; Shih, K.; Eckner, S.; Hattox, J.; Adams, A. S.; Rosendahl, R.; Faanes, R.; Eckner, R.; Koup, R.; Sullivan, J. Science, 1990, 250, 1411. Hargrave, K.; Schmidt, G.; Engel, W.; Trummlitz, G.; Eberlein, W. 5,11-Dihydro-6H-dipyrido(3,2-b:2,3-e) (1,4) diazepines and their use in the prevention or treatment of HIV infection, 1991, EP 00429987. Richman, D.; Rosenthahl, A.; Skoog, M.; Eckner, R.; Chou, T.; Sabo, J.; Merluzzi, V. Antimicrob. Agents Chemother., 1991, 35, 305. Hargrave, K.; Proudfoot, J.; Grozinger, K.; Culles, E.; Kapadia, S.; Patel, U.; Fuchs, V.; Mauldin, S.; Vitous, J.; Behnke, M.; Klunder, J.; Pal, K.; Skiles, J.; McNeil, D.; Rose, J.; Chow, G.; Skoog, M.; Wu, J.; Schmidt, G.; Engel, W.; Eberlei, W.; Saboe, T.; Campbell, S.; Rosenthal, A.; Adams, J. J. Med. Chem., 1991, 34, 2231. Proudfoot, J.; Hargrave, K.; Kapadia, S.; Patel, U.; Grozinger, K.; McNeil, D.; Cullen, E.; Cardozo, M.; Tong, L.; Kelly, T.; Rose, J.; David, E.; Mauldin, S.; Fuchs, V.; Vious, J.; Hoermann, M.; Klunder, J.; Raghavan, P.; Skiles, J.; Mui, P.; Richman, D.; Sullivan, J.; Shi, C.; Grob, P.; Adams, J. J. Med. Chem., 1995, 38, 4830. Mui, P.; Jacober, S.; Hargrave, K.; Adams, J. J. Med. Chem., 1992, 35, 201. Schafer, W.; Friebe, W.; Leinert, H.; Mertens, A.; Poll, T.; de Saal, W.; Zilch, H.; Nuber, B.; Ziegler, M. J. Med. Chem., 1993, 36, 726. Cheeseman, S. H.; Hatox, S.; McLaughlin, M.; Koup, R.; Andrew, C.; Bova, C.; Pav, J.; Roy, T.; Sullivan, J.; Keirns, J. Antimicob. Agents Chemother., 1993, 37, 178. Havlir, D.; Cheeseman, S.H.; McLqughlin, M.; Murphy, R.; Erice, A.; Spector, S.; Greenough, T.; Sullivan, J.; Hall.; D.; Myers, M. J. Infect. Dis., 1995, 171, 537. van Leth, F.; Phanuphak, P.; Ruxrungtham, K.; Baraldi, E.; Miller, Gazzard, B.; Cahn, P.; Lalloo, U.G.; van der Westhuizen, I.P.; Malan, D.R.; Johnson, M.A.; Santos, B.R.; Mulchacy, F.; Wood, R.; Levi, G.C.; Reboredo, G.; Squires, K.; Cassetti, I.; Petit, D.; Raffi, F.; Katlama, C.; Murphy, R.L.; Horban, A.; Dam, J.P.; Hassink, E.; van Leeuwen, R.; Robinson, P.; Wit, F.W.; Lange, J.M.A. Lancet, 2004, 363, 1253. See the black box in the Viramune drug datasheet at www.bidocs.com/renet:/Prescribing+Information/PIS/Viramune/Vi ramune.pdf. Havlir, D.; McLaughlin, M.M.; Richman, D.D. J. Infect. Dis., 1995, 172, 1379. Johnson, J.A.; Li, J.-F.; Morris, L.; Martinson, N.; Gray, G.; McIntyre, J.; Heneine, W. J. Infect. Dis., 2005, 192, 16. Romero, D.; Mitchell, M.; Thomas, R.; Palmer, J.; Tarpley, W.; Aristoff, P.; Smith, H. Diaromatic substituted anti-AIDS compounds, 1989, WO09109849. Duewke, T.; Kezdy, F.; Waszak, G.; Deibel, M.; Tarpley, W. J. Biol. Chem., 1992, 267, 27. Romero, D.; Morge, R.; Genin, M.; Bile, C.; Busso, M.; Resnick, L.; Althaus, I.; Reusser, F.; Thomas, R.; Tarpley, W. J. Med. Chem., 1993, 36, 1505.

116 Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2 [65] Dueweke, T.; Poppe, S.; Romero, D.; Swaney, S.; So, A.; Downey, K.; Althaus, I.; Reusser, F.; Buso, M.; Resnick, L.; Mayer, D.; Lane, J.; Aristoff, P.; Thomas, R.; Tarpley, W. Antimicrob. Agents Chemother., 1993, 37, 1127. Romero, D.; Morge, R.; Biles, C.; Pena, N.; May, P.; Palmer, J.; Johnson, P.; Smith, P.; Busso, M.; Tan, C.; Voorman, R.; Reusser, F.; Althaus, I.; Downey, K.; So, A.; Resnick, L.; Tarpley, W.; Aristof, P. J. Med. Chem., 1994, 37, 999. Genin, M.; Poel, T.; Yagi, Y.; Biles, C.; Althaus, I.; Keiser, B.; Kopta, L.; Friis, J.; Reusser, F.; Adams, W.; Olmsted, R.; Voorman, R.; Thomas, R.; Romero, D. J. Med. Chem., 1996, 39, 5267. Romero, D.; Olmsted, R.; Poel, T.; Morge, R.; Biles, C.; Keiser, B.; Kopta, L.; Friis, J.; Hosley, J.; Stefanski, K.; Wishhka, D.; Evans, D.; Moris, J.; Stehle, R.; Sharma, S.; Yagi, Y.; Voorman, R.; Adams, W.; Tarpley, W.; Thomas, R. J. Med. Chem., 1996, 39, 3769. Genin, M.; Poel, T.; May, P.; Kopta, L.; Yagi, Y.; Olmsted, R.; Friis, J.; Voorman, R.; Adams, W.; Thomas, R.; Romero, D. J. Med. Chem., 1999, 42, 4140. Esnouf, R.; Ren, J.; Hopkins, A.; Ross, C.; Jones, Y.; Stammers, D.; Stuart, D. Proc. Natl. Acad. Sci. USA, 1997, 94, 3984. Morse, G.; Fischl; M.; Shelton, M.; Cox. S.; Driver, M.; deRemer, M.; Freimuth, W. Antimicrob. Agents Chemother., 1997, 41, 169. Smith, P.; Dicenzo, R.; Morse, G. Clin. Pharmacokinet., 2001, 40, 893. Staton, B.; Johnson, M.; Friiis, J. J. Chrom. B Biomed. Sci. Appl., 1995, 668, 99. Moltke, L.L.; Greenblatt, D.J.; Granda, B.W.; Giancarlo, G.M.; Duan, S.X.; Daily, J.P.; Harmatz, J.S.; Shader, R.I. Clin. Pharmacol. Ther., 2000, 67, 158 (PIII-64). Vandamme, A.; van Vaerenbergh, K.; de Clercq, E. Antivir. Chem. Chemother., 1998, 9, 187. Young, S. D.; Britcher, S. F.; Payne, L. S.; tran, L. O.; Lumma, W. C.; Jr. Benzoxazinones as inhibitors of HIV reverse transcriptase, 1994, WO 09403440. Young, S.; Britcher, S.; Tran, L.; Payne, L.; Lumma, W.; Lyle, T.; Huff, J.; Anderson, P.; Olsen, D.; Carroll, S.; Pettibone, D.; OBrien, J.; Ball, R.; Balani, S.; Lin, J.; Che, I.; Schleif, W.; Sardana, V.; Long, W.; Byrnes, V.; Emini, E. Antimicrob. Agents Chemother., 1995, 39, 2602. Tucker, T.; Lyle, T.; Wiscount, C.; Britcher, S.; Young, S.; Sanders, W.; Lumma, W.; Goldman, M.; OBrien, J.; Ball, R.; Homnick, C.; Schleif, W.; Emini, E.; Huff, J.; Anderson, P. J. Med. Chem., 1994, 37, 2437. Patel, M.; McHugh, R.; Cordova, B.; Klabe, R.; Erickson-Viitanen, S.; Trainor, G.; Ko, S. Bioorg, Med. Chem. Lett., 1999, 9, 3221. Patel, M.; Ko, S.; McHugh, R.; Markwalder, J.; Scrivastava, A.; Cordova, B.; Klabe, R.; Erickson-Viitanen; S.; Trainor, G.; Seitz, S. Bioorg. Med. Chem. Lett., 1999, 9, 2805. Corbett, J.W.; Ko, S.S.; Rodgers, J.D.; Jeffrey, S.; Bacheler, L.T.; Klabe, R.M.; Diamond, S.; Lai, C.-M.; Rabel, S.R.; Saye, J.A.; Adams, S.P.; Trainor, G.L.; Anderson, P.S.; Erickson-Viitanen, S.K. Antimicrob. Agents Chemother., 1999, 43, 2893. Ren, J.; Milton, J.; Weaver, K.; Short, S.; Stuart, D.; Stammers, D. Structure, 2000, 8, 1089. Balani, S.K.; Kauffman, L.R.; DeLuna, F.A.; Lin, J.H. Drug Metabol. Dispos., 1999, 27, 41. See the full prescribing information for efavirenz at www.sustiva.com Markwalder, J.A.; Christ, D.D.; Mutlib, A.; Cordova, B.C.; Klabe, R.M.; Seitz, S.P. Bioorg. Med. Chem. Lett., 2001, 11, 619. Manfredi, R.; Calza, L.; Chiodo, F. J. Antimicrob. Chemother., 2002, 49, 723. Yoakim, C.; Bonneau, P.R.; Deziel, R.; Doyon, L.; Duan, J.; Guse, I.; Landry, S.; Malenfant, E.; Naud, J.; Ogilvie, W.W.; OMeara, J.A.; Plante, R.; Simoneau, B.; Thavonekham, B.; Bs, M.; Cordingley, M.G. Bioorg. Med. Chem. Lett., 2004, 14, 739. OMeara, J.A.; Yoakim, C.; Bonneau, P.R.; Bs, M.; Cordingley, M.G.; Deziel, R.; Doyon, L.; Duan, J.; Garneau, M.; Guse, I.; Landry, S.; Malenfant, E.; Naud, J.; Ogilve, W.W.; Thavonekham, B.; Simoneau, B. J. Med. Chem., 2005, 48, 5580. Bonneau, P.; Robinson, P.A.; Duan, J.; Doyon, L.; Simoneau, B.; Yoakim, C.; Garneau, M.; Bos, M.; Cordingley, M.; Brenner, B.; Spira, B.; Wainberg, M.; Huang, F.; Drda, K.; Ballow, C.; KoenenBergmann, M.; Mayers, D.L. 12th Conference on Retroviruses and Opportunistic Infections 2005, abstract 558. [90]

Sahlberg and Zhou Janssen, P.A.J.; Lewi, P.J.; Arnold, E.; Daeyaert, F.; de Jonge, M.; Heeres, J.; Koymans, L.; Vinkers, M.; Guillemont, J.; Pasquier, E.; Kukla, M.; Ludovici, D.W.; Andries, K.; de Bethune, M.-P.; Pauwels, R.; Das, K.; Clark, A.D., Jr; Volovik Frenkel, Y.; Hughes, S.H.; Medaer, B.; De Knaep, F.; Bohets, H.; De Clerk, F.; Lampo, A.; Williams, P.; Stoffels, P. J. Med. Chem., 2005, 48, 1901. van t Klooster, G.A.E., Gruzdev, B.; Horban, A.; BoronKaczmarska, A.; Gille, D.; Comhaire, S.; van der Geest, R.; Pauwels, R. Antivir. Res., 2001, 50:1, A41. See IPMs home page at www.ipm-microbicides.org Malcolm, R.K.; Woolfson, A.D.; Toner, C.F.; Morrow, R.J.; McCullagh, S.D. J. Antimicrob. Chemother., 2005, 56 , 954. Ludovici, D.W.; De Corte, B.L.; Kukla, M.J.; Ye, H.; Ho, C. Y.; Lichtenstein, M.A.; Kawash, R.W.; Andriens, K.; de Bethune, M.P,; Azijn, H.; Pauwels, R.; Lewi, P.J.; Heeres, J.; Koymans, L. M.H.; de Jonge, M.R.; Van Aken, K.J.A.; Daeyaert, F.F.D.; Das, H.; Arnold, E.; Janssen, P.A. Bioorg. Med. Chem. Lett., 2001, 11, 2235. Das, K.; Clark, A.D., Jr.; Lewi, P.J.; Heeres, J.; de Jonge, M.; Koymans, L.M.H.; Vinkers, H.M.; Daeyaert, F.; Ludovici, D.W.; Kukla, M.L.; De Corte, B.; Kavash, R.W.; Ho, C.Y.; Ye, H.; Lichtenstein, M.A.; Andries, K.; Pauwels, R.; De Bethune, M.-P.; Boyer, P-L.; Clark, P.; Hughes, S.H.; Janssen, P.A.J.; Arnold, E. J. Med. Chem., 2004, 47, 2550. Andriens, K.; Azijn, H.; Thielemans, T.; Ludovici, D.; Kukla, M.; Heeres, J.; Janssen, P.; De Corte, B.; Vingerhoets, J.; Pauwels, R.; de Bethune, M.-P. Antimicrob. Agents Chemother., 2004, 48, 4680. Vingerhoets, L.; Azijn, H.; Fransen, E.; De Baere, I.; Smeulders, L.; Jochmans, D.; Andriens, K.; Pauwels, R.; Bethune, M.-P. J. Virol., 2005, 79, 12773. Press release from Tibotec 2005, November 29. Gazzard, B.G.; Pozniak, A-L.; Rosenbaum, W.; Yeni, G.P.; Staszewski, S.; Arasteh, K.; De Dier, K.; Peeters, M.; Woodfall, B.; Stebbing, J.; vant Klooster, G.A.E. AIDS, 2003, 17, 49. Sankatsing, S.U.C.; Weverling, G.J.; Peeters, M.; vant Klooster, G.; Gruzdev, B.; Rakhmanova, A.; Danner, S.A.; Jurrians, S.; Prins, J.-M.; Lange, J.M.A. AIDS, 2003, 17, 2623. Gruzdev, B.; Rakhmanova, A.; Doubovskaya, E.; Yakovlev, A.; Peeters, M.; Rinehart,, A.; de Dier, K.; Baede-Van Dijk, P.; Parys, W.; vant Klooster, G. AIDS, 2003, 17, 2487. Guilllemont, J.; Paquier, E.; Palandjian, P.; Vernier, D.; Gaurrand, S.; Lewi, P.J.; Heeres, J.; de Jonge, M.R.; Koymans, L.M.H.; Daeyaert, F.F.D.; Vinkers, M.H.; Arnold, E.; Das, K.; Pauwels, R.; Andries, K.; de Bethune, M.-P.; Bettens, E.; Hertogs, K.; Wigerinck, P.; Timmerman, P.; Janssen, P.A.J. J. Med. Chem., 2005, 48, 2072. Goebel, F.; Yakovlev, A.; Pozniak, A. L.; Vinogradova, E.; Boogaerts, G.; Hoetelmans, R.; de Bethune, M.-P.; Peeters, M.; Woodfall, B. AIDS, 2006, 20, 1721. Fujiwara, T.; Sato, A.; El-Farrash, M.; Miki, S.; Abe, K.; Isaka, Y.; Kodama, M.; Wu, Y.; Chen, L. B.; Harada, H.; Sugimoto, H.; Hatanaka, M.; Hinuma, Y. Antimicrob. Agents Chemother., 1998, 42, 1340. Gewurz, B.E.; Jacobs, M.; Proper, L.A.; Dahl, T.A.; Fujiwara, T.; Dezube, B.J. J. Infect. Dis., 2004, 190, 1957. Bu, H.-Z.; Pool, W. F.; Wu, E.Y.; Raber, S.R.; Amantea, M.A.; Shetty, B.V. Drug Metabol. Dispos.; 2004, 32, 689. Press release from Pfizer 2005, July 01. Chen, J.M.; Chen, X.; Kim, C.U.; Lee, W.A.; Tario, J.D.; Xu, L.; Nelson, P.H. Non nucleoside reverse transcriptase inhibitors, 2003, WO 03091264. De Clercq, E.; van Aerschot, A.; Herdewijn, O.; Lagoja, I.; Pannecoucque, C. HIV inhibiting N-aminoimidazole derivatives, 2002, WO 02/068395. Chan, J.H.; Freeman, G.A.; Romines, K.R.; Schaller, L.T.; Cowan, J.R.; Gonzales, S.S.; Lowell, G.S.; Andrews III, C.W.; Reynolds, D.J.; St Clair, M.; Hazen, R.J.; Ferris, R.G.; Creech, K.L.; Roberts, G.B.; Short, S.A.; Weaver, K.; Koszalka, G.W.; Boone, L.R. J. Med. Chem., 2004, 47, 1175. Romines, K.R.; Freeman, G.A.; Schaller, L.T.; Cowan, J.R.; Gonzales, S.S.; Tidwell, J.H.; Andrews III, C.W.; Reynolds, D.J.; Stammers, D.K.; Hazen, R.J.; Ferris, R.G.; Short, S.A.; Chan, J.H.; Boone, L.R. J. Med. Chem., 2006, 49, 727. Ferris, R.G.; Hazen, R.J.; Roberts, G.B.; St Clair, M.H.; Chan, J.H.; Romines, K.R.; Freeman, G.A.; Tidwell, J.H.; Schaller, L.T.;

[66]

[91]

[67]

[92] [93] [94]

[68]

[69] [70] [71] [72] [73] [74]

[95]

[96]

[97] [98] [99] [100]

[75] [76] [77]

[101] [102]

[78]

[79] [80] [81]

[103]

[104]

[82] [83] [84] [85] [86] [87]

[105] [106] [107] [108]

[109] [110]

[88]

[111]

[89]

[112]

Development of Non-Nucleoside Reverse Transcriptase Inhibitors Cowan, J.R.; Short, S.A.; Weaver, K.L.; Selleseth, D.W.; Moniri, K.R.; Boone, L.R. Antimicrob. Agents Chemother., 2005, 49, 4046. Becker, S.; Lalezari, J.; Walworth, C.; Kumar, P.; Cade, J.; NgCashin, J.; Kim, Y.; Scott, J.; St. Clair, M.; Jones, L.; Symonds, W . 3rd IAS Conference on HIV Pathogenesis and Treatment 2005, abstract WePe6. 2C03. Bell, F.W.; Cantrell, A.S.; Hgberg, M.; Jaskunas, S.R.; Johansson, N.G.; Jordan, C.L.; Kinnick, M. D.; Lind, P.; Morin, Jr. J.M.; Noren, R.; berg, B.; Palkowitz, J.A.; Parrish, C.A.; Pranc, P.; Sahlberg, C.; Ternansky, R.J.; Vasileff, R.T.; Vrang, L.; West, S.J.; Zhang, H.; Zhou, X.-X. J. Med. Chem., 1995, 38, 4929. Cai, S.; Dimitroff, M.; McKennon, T.;Reider, M.; Robarge, L.; Ryckman, D.; Shang, X.; Therrien, J. Org. Process Res. Dev., 2004, 8, 353. See population councils homepage at www.popcouncil.org Lindstroem, S.; Sahlberg, C.; Wallberg, H.; Kalyanov, G.; Oden, L.; Naeslund, L. Tricycloalkatrienes as non-nucleoside reverse transcriptase inhibitors, 2002, WO 2002070516. Uckun, F.M.; Venkatachalam, T.K. Piperidinethyl-, phenoxyethyl,and beta-fluorophenethyl-substituted thiourea compounds with potent anti-HIV activity, 2002, US 2002/0151568. Venkatachalam, T.K; Mao, C.; Uckun, F.M. Bioorg. Med. Chem., 2004, 12, 4275. DCruz, O.J.; Uckun, F.M. Mol. Hum. Reprod., 2005, 11 , 767.

Anti-Infective Agents in Medicinal Chemistry, 2008, Vol. 7, No. 2 [121] [122]

117

[113]

[123]

[114]

[124]

[115] [116] [117] [118]

[125] [126]

[127] [128]

[119] [120]

[129]

Miyasaka, T.; Tanaka, H.; Baba, M.; Hayakawa, H.; Walker, R. T.; Balzarini, J.; De Clercq, E. J. Med. Chem., 1989, 32, 2507. Baba, M.; Shigeta, S.; Yuasa, S.; Takashima, H.; Sekiya, K.; Ubasawa, M.; Tanaka, H.; Miyasaka, T.; Walker, T.; De Clercq, E. Antimicrob. Agents Chemother., 1994, 38, 688. Szczech, G.M.; Furman, P.; Painter, G.R.; Barry, D.W.; BorrotoEsoda, K.; Grizzle, T.B.; Blum, M.R.; Sommadossi, J.-P.; Endoh, R.; Niwa, T.; Yamamoto, M.; Moxham, C. Antimicrob. Agents Chemother., 2000, 44, 123. Buckheit, R.W. Jr.; Watson, K.; Fliakas-Boltz, V.; Russell, J.; Loftus, T.L.; Osterling, M.C.; Turpin, J.A.; Pallansch, L.A.; White, E.L.; Lee, J.-W.; Lee, S.-H.; Oh, J.-W.; Kwon, H.-S.; Chung, S.-G.; Cho, E.-H. Antimicrob. Agents Chemother., 2001, 45, 393. Press release from ImQuest Pharmaceuticals 2006, February 28. Ragno, R.; Mai, A.; Sbardella, G.; Artico, M.; Massa, S.; Musiu, C.; Mura, M.; Marturana, F.; Cadeddu, A.; La Colla, P. J. Med. Chem., 2004, 47, 928. Wang, Z.; Wu, B.; Kuhen, K.L.; Bursulaya, B.; Nguyen, T.N.; Nguyen, D.G.; He, Y. Bioorg. Med. Chem. Lett., 2006, 16, 4174. De La Rosa, M.; Kim, H.W.; Gunic, E.; Jenket, C.; Boyle, U.; Koh, Y.-H.; Korboukh, I.; Allan, M.; Zhang, W.; Chen, H.; Xu, W.; Nilar, S.; Yao, N.; Hamatake, R.; Lang. S.A.; Hong, Z.; Zhang, Z.; Giradet, L.-L. Bioorg. Med. Chem. Lett., 2006, 16, 4444. Press release from Ardea biosciences 2006, December 22.

Received: February 20, 2007

Revised: April 13, 2007

Accepted: April 15, 2007

También podría gustarte