Recent advances in DAPYs and related analogues as HIV-1 NNRTIs

Current Medicinal Chemistry

Volumn 18, Issue 3, 2011, Pages 359-376

  Chen, Xuwang ^a   Zhan, Peng ^a   Li, Dongyue ^a   De Clercq, Erik ^b   Liu, Xinyong ^a  

^a SHANDONG UNIVERSITY   (China)

^b REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

Author keywords

DaPY; Drug design; Drug resistance; HIV 1; NNRTIs; TMC125; TMC278

Indexed keywords

9 CHLORO 4,5,6,7 TETRAHYDRO 5 METHYL 6 (3 METHYL 2 BUTENYL)IMIDAZO[4,5,1 JK][1,4]BENZODIAZEPINE 2(1H) THIONE; DAPIVIRINE; DELAVIRDINE; EFAVIRENZ; ETRAVIRINE; IDX 899; LOVIRIDE; NEVIRAPINE; NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR; R 100943; R 106168; R 14458; RILPIVIRINE; RNA DIRECTED DNA POLYMERASE; TIVIRAPINE; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; ANTIVIRAL THERAPY; BIOLOGY; CRYSTALLOGRAPHY; DRUG CONFORMATION; DRUG CYTOTOXICITY; DRUG RESISTANCE; DRUG SPECIFICITY; DRUG TARGETING; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HYDROGEN BOND; NONHUMAN; PHASE 3 CLINICAL TRIAL (TOPIC); REVIEW; VIRUS STRAIN; WILD TYPE;

EID: 79251472419     PISSN: 09298673     EISSN: None     Source Type: Journal    
DOI: 10.2174/092986711794839142     Document Type: Review

References (82)

1. UNAIDS, global AIDS report, 2009.
2. Hirschel, B.; Francioli, P. Progress and problems in the fight against AIDS. N. Engl J. Med., 1998, 338, 906-908.
3. De Clercq, E. New developments in anti-HIV chemotherapy. Curr. Med. Chem., 2001, 8, 1543-1572. (Pubitemid 33076802)
4. Martins, S.; Ramos, M.J.; Fernandes, P.A. The current status of the NNRTI family of antiretrovirals used in the HAART regime against HIV infection. Curr. Med. Chem., 2008, 15, 1083-1095.
5. Zhan, P.; Liu, X.Y.; Li, Z.Y. Recent advances in the discovery and development of novel HIV-1 NNRTI platforms: 2006-2008 update. Curr. Med. Chem., 2009, 16, 2876-2889.
6. Ilina, T.; Parniak, M.A. Inhibitors of HIV-1 reverse transcriptase. Adv. Pharmacol., 2008, 56, 121-167.
7. Jochmans, D. Novel HIV-1 reverse transcriptase inhibitors. Virus Res., 2008, 134, 171-185.
8. De Corte, B.L. From 4,5,6,7-tetrahydro-5-methylimidazo [4,5,1- jk](1,4)benzodiazepin-2(1H)-one (TIBO) to etravirine(TMC125): Fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase. J. Med. Chem., 2005, 48, 1689-1696.
9. Heeres, J.; Lewi, P.J. The medicinal chemistry of the DATA and DAPY series of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Adv. Antiviral Drug Des., 2007, 5, 213-242.
10. De Clercq, E. The design of drugs for HIV and HCV. Nat. Rev. Drug Discov., 2007, 6, 1001-1018.
11. Sax, P.E. FDA approval: Etravirine. AIDS Clin. Care, 2008, 20, 17-18.
12. Seminari, E.; Castagna, A.; Lazzarin, A. Etravirine for the treatment of HIV infection. Expert Rev. Anti Infect. Ther., 2008, 6, 427-433.
13. Hsiou, Y.; Ding, J.; Das, K.; Clark, A.D.; Hughes, S.H.; Arnold, E. Structure of unliganded HIV-1 reverse transcriptase at 2.7 Å resolution: Implications of conformational changes for polymerization and inhibition mechanisms. Structure, 1996, 4, 853-860.
14. Sarafianos, S.G.; Marchand, B.; Das, K.; Himmel, D.M.; Parniak, M.A.; Hughes, S.H.; Arnold, E. Structure and function of HIV-1 reverse transcriptase: Molecular mechanisms of polymerization and inhibition. J. Mol. Biol., 2009, 385, 693-713.
15. Pauwels, R.; Andries, K.; Desmyter, J.; Schols, D.; Kukla, M.J.; Breslin, H.J.; Raeymaekers, A.; Van Gelder, J.; Woestenborghs, R.; Heykants, J.; Schellekens, K.; Janssen, M.A.C.; De Clercq, E.; Janssen, P.A.J. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature, 1990, 343, 470-474. (Pubitemid 120028562)
16. Kukla, M.J.; Breslin, H.J.; Diamond, C.J.; Grous, P.P.; Ho, C.Y.; Miranda, M.; Rodgers, J.D.; Sherrill, R.G.; De Clercq, E.; Pauwels, R.; Andries, K.; Moens, L.J.; Janssen, M.A.C.; Janssen, P.A.J. Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5- methylimidazo [4,5,1-jk] [1,4]benzodiazepin-2- (1H)-one (TIBO) derivatives 2. J. Med. Chem., 1991, 34, 3187-3197.
17. Kukla, M.J.; Breslin, H.J.; Pauwels, R.; Fedde, C.L.; Miranda, M.; Scott, M.K.; Sherrill, R.G.; Raeymaekers, A.; Van Gelder, J.; Andries, K.; Janssen, K.; Janssen, M.A.C.; De Clercq, E.; Janssen, P.A.J. Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5- methylimidazo [4,5,1-jk] [1,4] benzodiazepin-2- (1H)-one (TIBO) derivatives. J. Med. Chem., 1991, 34, 746-751.
18. Pauwels, R.; Andries, K.; Debyser, Z.; Van Daele, P.; Schols, D.; Stoffels, P.; De Vreeze, K.; Woestenborghs, R.; Vandamme, A.M.; Janssen, C.G.M.; Anne, J.; Cauwenbergh, G.; Desmyter, J.; Heykants, J.; Janssen, M.A.C.; De Clercq, E.; Janssen, P.A.J. Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of β-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase. Proc. Natl. Acad. Sci. USA, 1993, 90, 1711-1715. (Pubitemid 23069926)
19. Romero, D.L.; Morge, R.A.; Genin, M.J.; Biles, C.; Busso, M.; Resnick, L.; Althaus, I.W.; Reusser, F.; Thomas, R.C.; Tarpley, W.G. Bis(heteroaryl) piperazine (BHAP) reverse transcriptase inhibitors: Structure-activity relationships of novel substituted indole analogues and the identification of 1- [(5-methanesulfonamido-1Hindol- 2-yl)-carbonyl]-4- [3- [(1-methylethyl)amino]- pyridinyl]piperazine monomethanesulfonate (U-90152S), a secondgeneration clinical candidate. J. Med. Chem., 1993, 36, 1505-1508.
20. Ludovici D.W.; Kukla M.J.; Grous P.G.; Krishnan, S.; Andries, K.; de Béthune, M.-P.; Azijn, H.; Pauwels, R.; De Clercq, E.; Arnold, E.; Janssen, P.A. Evolution of anti-HIV drug candidates. part 1: From β-anilinophenylacetamide (β-APA) to imidoyl thiourea (ITU). Bioorg. Med. Chem. Lett., 2001, 11, 2225-2228.
21. Das, K.; Clark, A.D.; Lewi, P.J.; Heeres, J.; De Jonge, M.R.; Koymans, L.M.; Vinkers, H.M.; Daeyaert, F.; Ludovici, D.W.; Kukla, M.J.; De Corte, B.; Kavash, R.W.; Ho, C.Y.; Ye, H.; Lichtenstein, M.A.; Andries, K.; Pauwels, R.; de Béthune, M.-P.; Boyer, P.L.; Clark, P.; Hughes, S.H.; Janssen, P.A.; Arnold, E. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J. Med. Chem., 2004, 47, 2550-2560.
22. Ludovici, D.W.; Kavash, R.W.; Kukla, M.J.; Ho, C.Y.; Ye, H.; De Corte, B.L.; Andries, K.; de Béthune, M.-P.; Azijn, H.; Pauwels, R.; Moereels, H.E.; Heeres, J.; Koymans, L.M.; de Jonge, M.R.; Van Aken, K.J.; Daeyaert, F.F.; Lewi, P.J.; Das, K.; Arnold, E.; Janssen, P.A. Evolution of anti-HIV drug candidates part 2: Diaryltriazine (DATA) analogues. Bioorg. Med. Chem. Lett., 2001, 17, 2229-2234. (Pubitemid 32781672)
23. Ludovici, D.W.; De Corte, B.L.; Kukla, M.J.; Ye, H.; Ho, C.Y.; Lichtenstein, M.A.; Kavash, R.W.; Andries, K.; de Béthune, 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, K.; Arnold, E.; Janssen, P.A.J. Evolution of anti-HIV drug candidates. part 3: Diarylpyrimidine (DAPY) analogues. Bioorg. Med. Chem. Lett., 2001, 11, 2235-2239. (Pubitemid 32781673)
24. 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.; Andries, K.; de Béthune, M.-P.; Pauwels, R.; Das, K.; Clark, A.D.; Jr.; Frenkel, Y.V.; Hughes, S.H.; Medaer, B.; De Knaep, F.; Bohets, H.; De Clerck, F.; Lampo, A.; Williams, P.; Stoffels, P. In search of a novel anti-HIV drug: Multidisciplinary coordination in the discovery of 4- [ [4- [ [4- [(1E)-2- cyanoethenyl]-2,6-dimethylphenyl]amino]- 2pyrimidinyl]amino] benzonitrile (R278474, rilpivirine). J. Med. Chem., 2005, 48, 1901-1909.
25. Guillemont, J.; Pasquier, 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 Béthune, M.-P.; Bettens, E.; Hertogs, K.; Wigerinck, P.; Timmerman, P.; Janssen, P.A.J. Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1. J. Med. Chem., 2005, 48, 2072-2079.
26. Feng, X.Q.; Liang, Y.H.; Zeng, Z.S.; Chen, F.E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. Structural modifications of DAPY analogues with potent anti-HIV-1 activity. Chem. Med. Chem., 2009, 4, 219-224.
27. Liang, Y.H.; Feng, X.Q.; Zeng, Z.S.; Chen, F.E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. Design, synthesis, and SAR of naphthyl-substituted diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Chem. Med. Chem., 2009, 4, 1537-1545.
28. Liang, Y.H.; Zeng, Z.S.; Liu, Z.Q.; Feng, X.Q.; Chen, F.E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. Synthesis and anti-HIV activity of 2-naphthyl substituted DAPY analogues as non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem., 2010, 10.1016/j.bmc.2010.05.036
29. Di Fabio, S.; Van Roey, J.; Giannini, G.; van den Mooter, G.; Spada, M.; Binelli, A.; Pirillo, M.F.; Germinario, E.; Belardelli, F.; de Bethune, M.-P.; Vella, S. Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel formulation. AIDS, 2003, 17, 1597-1604.
30. Van Herrewege, Y.; Vanham, G.; Michiels, J.; Fransen, K.; Kestens, L.; Andries, K.; Janssen, P.; Lewi, P. A series of diaryltriazines and diarylpyrimidines are highly potent non-nucleoside reverse transcriptase inhibitors with possible applications as microbicides. Antimicrob. Agents Chemother., 2004, 48, 3684-3689.
31. Feng, X.Q.; Zeng, Z.S.; Liang, Y.H.; Chen, F.E.; Pannecouque, C.; Balzarini, J.; De Clercq, E. Synthesis and biological evaluation of 4-(hydroxyimino)arylmethyl diarylpyrimidine analogues as potential non-nucleoside reverse transcriptase inhibitors against HIV. Bioorg. Med. Chem., 2010, 18, 2370-2374.
32. Zeng, Z.S.; Liang, Y.H.; Feng, X.Q.; Chen, F.E.; Pannecouque, C.; Balzarini, J.; De Clercq, E. Lead optimization of diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Chem. Med. Chem., 2010, 5, 837-840.
33. Girardet, J.L.; Koh, Y.H.; Shaw, S.; Kin, H.W. Diaryl-purine, azapurines and -deazapurines as non-nucleoside reverse transcriptase inhibitors for treatment of HIV. Patent WO 2006122003, 2006.
34. Udier-Blagović, M.; Tirado-Rives, J.; Jorgensen, W.L. Validation of a model for the complex of HIV-1 reverse transcriptase with non-nucleoside inhibitor TMC125. J. Am. Chem. Soc., 2003, 125, 6016-6017.
35. Lansdon, E.B.; Brendza, K.M.; Hung, M.; Wang, R.; Mukund, S.; Jin, D.; Birkus, G.; Kutty, N.; Liu, X.H. Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278): Implications for drug design. J. Med. Chem., 2010, 53, 4295-4299.
36. Brotherton-Pleiss, C.E.; Kertesz, D.J.; Yang, M.M. Non-nucleoside reverse transcriptase inhibitors. Patent WO 2008071587, 2008.
37. Kertesz, D.J.; Brotherton-Pleiss, C.; Yang, M.M.; Wang, Z.G.; Lin, X.F.; Qiu, Z.X.; Hirschfeld, D.R.; Gleason, S.; Mirzadegan, T.; Dunten, P.W.; Harris, S.F.; Villaseñor, A.G.; Hang, J.Q.; Heilek, G.M.; Klumpp, K. Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-benzyl derivatives with broad potency against resistant mutant viruses. Bioorg. Med. Chem. Lett., 2010, 20, 4215-4218.
38. Tang, G.; Kertesz, D.J.; Yang, M.; Lin, X.; Wang, Z.; Li, W.; Qiu, Z.; Chen, J.; Mei, J.; Chen, L.; Mirzadegan, T.; Harris, S.F.; Villaseñor, A.G.; Fretland, J.; Fitch, W.L.; Hang, J.Q.; Heilek, G.; Klumpp, K. Exploration of piperidine-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Phenyl derivatives with broad potency against resistant mutant viruses. Bioorg. Med. Chem. Lett., 2010, 20, 6020-6023.
39. Zhan, P.; Liu, X.Y.; Li, Z.Y.; Pannecouque, C.; De Clercq, E. Design strategies of novel NNRTIs to overcome drug resistance. Curr. Med. Chem., 2009, 16, 3903-3917.
40. Morphy, R.; Rankovic, Z. Designing multiple ligands-medicinal chemistry strategies and challenges. Curr. Pharm. Des., 2009, 15, 587-600.
41. Zhan, P.; Liu, X.Y. Designed multiple ligands: An emerging anti- HIV drug discovery paradigm. Curr. Pharm. Des., 2009, 15, 1893-1917.
42. Mordant, C.; Schmitt, B.; Pasquier, E.; Demestre, C.; Queguiner, L.; Masungi, C.; Peeters, A.; Smeulders, L.; Bettens, E.; Hertogs, K.; Heeres, J.; Lewi, P.; Guillemont J. Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains. Eur. J. Med. Chem., 2007, 42, 567-579.
43. Kohlstaedt, L.A.; Wang, J.; Friedman, J.M.; Rice, P.A.; Steitz, T.A. Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science, 1992, 256, 1783-1790.
44. Smerdon, S.J.; Jager, J.; Wang, J.; Kohlstaedt, L.A.; Chirino, A.J.; Friedman, J.M.; Rice, P.A.; Steitz, T.A. Structure of the binding site for non-nucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. USA, 1994, 91, 3911-3915. (Pubitemid 24139542)
45. Esnouf, R.M.; Ren, J.; Hopkins, A.L.; Ross, C.K.; Jones, E.Y.; Stammers, D.K.; Stuart, D.I. Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this non-nucleoside inhibitor. Proc. Natl. Acad. Sci. USA, 1997, 94, 3984-3989.
46. Ren, J.; Milton, J.; Weaver, K.L.; Short, S.A.; Stuart, D.I.; Stammers D.K. Structural basis for the resilience of efavirenz (DMP- 266) to drug resistance mutations in HIV-1 reverse transcriptase. Struct. Fold Des., 2000, 8, 1089-1094.
47. Lindberg, J.; Sigurdsson, S.; Lowgren, S.; Andersson, H.O.; Sahlberg, C.; Noréen R.; Fridborg K.; Zhang H.; Unge T. Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant. Eur. J. Biochem., 2002, 269, 1670-1677.
48. Ren, J.; Stammers, D.K. Structural basis for drug resistance mechanisms for non-nucleoside inhibitors of HIV reverse transcriptase. Virus Res., 2008, 134, 157-170.
49. Daeyaert, F.; de Jonge, M.; Heeres, J.; Koymans, L.; Lewi, P.; Vinkers, M.H.; Janssen, P.A. A pharmacophore docking algorithm and its application to the cross-docking of 18 HIV-NNRTI's in their binding pockets. Proteins, 2004, 54, 526-533.
50. Daszykowski, M.; Walczak, B.; Xu, Q.S.; Daeyaert, F.; de Jonge, M.R.; Heeres, J.; Koymans, L.M.; Lewi, P.J.; Vinkers, H.M.; Janssen, P.A.; Massart, D.L. Classification and regression trees-studies of HIV reverse transcriptase inhibitors. J. Chem. Inf. Comput. Sci., 2004, 44, 716-726.
51. Barreca, M.L.; Rao, A.; De Luca, L.; Zappal, M.; Monforte, A.M.; Maga, G.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Chimirri, A.; Monforte, P. Computational strategies in discovering novel non-nucleoside inhibitors of HIV-1 RT. J. Med. Chem., 2005, 48, 3433-3437.
52. Barreca, M.L.; De Luca, L.; Iraci, N.; Rao, A.; Ferro, S.; Maga, G.; Chimirri, A. Structure-based pharmacophore identification of new chemical scaffolds as non-nucleoside reverse transcriptase inhibitors. J. Chem. Inf. Model., 2007, 47, 557-562.
53. Das, K.; Bauman, J.D., Clark Jr., A.D., Frenkel, Y.V., Lewi, P.J., Shatkin, A.J., Hughes, S.H., Arnold, E. High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: Strategic flexibility explains potency against resistance mutations. Proc. Natl. Acad. Sci. USA, 2008, 105, 1466-1471.
54. Fattorusso, C.; Gemma, S.; Butini, S.; Huleatt, P.; Catalanotti, B.; Persico, M.; De Angelis, M.; Fiorini, I.; Nacci, V.; Ramunno, A.; Rodriquez, M.; Greco, G.; Novellino, E.; Bergamini, A.; Marini, S.; Coletta, M.; Maga, G.; Spadari, S.; Campiani, G. Specific targeting highly conserved residues in the HIV-1 reverse transcriptase primer grip region. design, synthesis, and biological evaluation of novel, potent, and broad spectrum NNRTIs with antiviral activity. J. Med. Chem., 2005, 48, 7153-7165.
55. Butini, S.; Brindisi, M.; Cosconati, S.; Marinelli, L.; Borrelli, G.; Coccone, S.S.; Ramunno, A.; Campiani, G.; Novellino, E.; Zanoli, S.; Samuele, A.; Giorgi, G.; Bergamini, A.; Mattia, M.D.; Lalli, S.; Galletti, B.; Gemma, S.; Maga, G. Specific targeting of highly conserved residues in the HIV-1 reverse transcriptase primer grip region. 2. stereoselective interaction to overcome the effects of drug resistant mutations. J. Med. Chem., 2009, 52, 1224-1228.
56. Ren, J.; Nichols, C.; Bird, L.E.; Fujiwara, T.; Sugimoto, H.; Stuart, D.I.; Stammers, D.K. Binding of the second generation nonnucleoside inhibitor S-1153 to HIV-1 reverse transcriptase involves extensive main chain hydrogen bonding. J. Biol. Chem., 2000, 275, 14316-14320.
57. Fang, C.; Bauman, J.D.; Das, K.; Remorino, A.; Arnold, E.; Hochstrasser, R.M. Two dimensional infrared spectra reveal relaxation of the non-nucleoside inhibitor TMC278 complexed with HIV- 1 reverse transcriptase. Proc. Natl. Acad. Sci. USA, 2008, 105, 1472-1477.
58. Hopkins, A.L.; Ren, J.; Milton, J.; Hazen, R.J.; Chan, J.H.; Stuart, D.I.; Stammers, D.K. Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties 1. J. Med. Chem., 2004, 47, 5912-5922. (Pubitemid 39517015)
59. Hopkins, A.L.; Ren, J.; Esnouf, R.M.; Willcox, B.E.; Jones, E.Y.; Ross, C.; Miyasaka, T.; Walker, R.T.; Tanaka, H.; Stammers, D.K.; Stuart, D.I. Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors. J. Med. Chem., 1996, 39, 1589-1600.
60. Lima, L.M.; Barreiro, E.J. Bioisosterism: A useful strategy for molecular modification and drug design. Curr. Med. Chem., 2005, 12, 23-49
61. Heeres, J.; de Jonge, M.R.; Koymans, L.M.H.; Daeyaert, F.F.D.; Vinkers, M.; Van Aken, K.J.A.; Arnold, E.; Das, K.; Kilonda, A.; Hoornaert, G.J.; Compernolle, F.; Cegla, M.; Azzam, R.A.; Andries, K.; de Béthune, M.-P.; Azijn, H.; Pauwels, R.; Lewi, P.J.; Janssen, P.A.J. Design, synthesis, and SAR of a novel pyrazinone series with non-nucleoside HIV-1 reverse transcriptase inhibitory activity. J. Med. Chem., 2005, 48, 1910-1918.
62. Silvestri, R.; Maga, G. Current state-of-the-art in preclinical and clinical development of novel non-nucleoside HIV-1 reverse transcriptase inhibitors. Expert Opin. Ther. Pat., 2006, 16, 939-962.
63. Saparpakorn, P.; Thammaporn, R.; Hannongbua, S. Use of 3D QSAR to investigate the mode of binding of pyrazinones to HIV-1 RT. Monatsh. Chem., 2009, 140, 587-594.
64. Tian, X.T.; Qin, B.J.; Lu, H.; Lai,W.H.; Jiang, S.B.; Lee, K.H.; Chen, C.H.; Xie, L. Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19, 5482-5485.
65. Viegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro, E.J.; Fraga C.A. Molecular hybridization: A useful tool in the design of new drug prototypes. Curr. Med. Chem., 2007, 14, 1829-1852.
66. Terasaka, T.; Kinoshita, T.; Kuno, M.; Nakanishi, I. A highly potent non-nucleoside adenosine deaminase inhibitor: Efficient drug discovery by intentional lead hybridization. J. Am. Chem. Soc., 2004, 126, 34-35.
67. Goldman, M.E.; Nunberg, J.H.; O'Brien, J.A.; Quintero, J.C.; Schleif, W.A.; Freund, K.F.; Gaul, S.L.; Saari, W.S.; Wai, J.S.; Hoffman, J.M.; Anderson, P.S.; Hupe, D.J.; Emini, E.A.; Stern, A.M. Pyridinone derivatives: Specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proc. Natl. Acad. Sci. USA, 1991, 88, 6863-6867.
68. Davey Jr, R.T.; Dewar, R.L.; Reed, G.F.; Vasudevachari, M.B.; Polis, M.A.; Kovacs, J.A.; Falloon, J.; Walker, R.E.; Masur, H.; Haneiwich, S.E.; O'Neill, D.G.; Decker, M.R.; Metcalf, J.A.; Deloria, M.A.; Laskin, O.L.; Salzman, N.; Lane, H.C. Plasma viremia as a sensitive indicator of the antiretroviral activity of L-697 661. Proc. Natl. Acad. Sci. USA, 1993, 90, 5608-5612.
69. Saag, M.S.; Emini, E.A.; Laskin, O.L.; Douglas, J.; Lapidus, W.I.; Schleif, W.A.; Whitley, R.J.; Hildebrand, C.; Byrnes, V.W.; Kappes, J.C.; Anderson, K.W.; Massari, F.E.; Shaw, G.M. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. N. Engl. J. Med., 1993, 329, 1065-1072.
70. Benjahad, A.; Courté, K.; Guillemont, J.; Mabire, D.; Coupa, S.; Poncelet, A.; Csoka, I.; Andries, K.; Pauwels, R.; de Béthune, M.P.; Monneret, C.; Bisagni, E.; Nguyen, CH.; Grierson, DS. 4- benzyl- and 4-benzoyl-3-dimethylaminopyridin-2(1H)-ones, a new family of potent anti-HIV agents: Optimization and in vitro evaluation against clinically important HIV mutant strains. J. Med. Chem., 2004, 47, 5501-5514.
71. Benjahad, A.; Croisy, M.; Monneret, C.; Bisagni, E.; Mabire, D.; Coupa, S.; Poncelet, A.; Csoka, I.; Guillemont, J.; Meyer, C.; Andries, K.; Pauwels, R.; de Béthune M.P.; Himmel, D.M.; Das, K.; Arnold, E.; Nguyen, C.H.; Grierson. D.S. 4-Benzyl and 4-benzoyl- 3-dimethylaminopyridin-2(1H)-ones: In vitro evaluation of new C- 3-amino-substituted and C-5,6-alkyl-substituted analogues against clinically important HIV mutant strains. J. Med. Chem., 2005, 48, 1948-1964.
72. Himmel, D.M.; Das, K.; Clark Jr, A.D.; Hughes, S.H.; Benjahad, A.; Oumouch, S.; Guillemont, J.; Coupa, S.; Poncelet, A.; Csoka, I.; Meyer, C.; Andries, K.; Nguyen, C.H.; Grierson, D.S.; Arnold, E. Crystal structures for HIV-1 reverse transcriptase in complexes with three pyridinone derivatives: A new class of non-nucleoside inhibitors effective against a broad range of drug-resistant strains. J. Med. Chem., 2005, 48, 7582-7591.
73. Storer R.; Alexandre F.R.; Dousson C.; Moussa A.M.; Bridges E.; Enantiomerically pure phosphoindoles as HIV inhibitors. Patent WO 2008042240, 2008.
74. Zhou X.J.; Pietropaolo K.; Damphousse D.; Belanger B.; Chen J.; Sullivan-Bólyai J.; Mayers, D. Single-dose escalation and multipledose safety, tolerability, and pharmacokinetics of IDX899, a candidate human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitor, in healthy subjects. Antimicrob. Agents Chemother., 2009, 53, 1739-1746.
75. Klibanov O.M.; Kaczor R.L. IDX-899, an aryl phosphinate-indole non-nucleoside reverse transcriptase inhibitor for the potential treatment of HIV infection. Curr. Opin. Investig. Drugs, 2010, 11, 237-245.
76. Park, H.; Lee, S. Free energy perturbation approach to the critical assessment of selective cyclooxygenase-2 inhibitors. J. Comput. Aided Mol. Des., 2005, 19, 17-31.
77. Reddy, M.R.; Erion, M.D. Relative binding affinities of fructose- 1,6-bisphosphatase inhibitors calculated using a quantum mechanics- based free energy perturbation method. J. Am. Chem. Soc., 2007, 129, 9296-9297.
78. Barreiro, G.; Kim, J.T.; Guimarães, C.R.; Bailey, C.M.; Domaoal, R.A.; Wang, L.; Anderson, K.S.; Jorgensen, W.L. From docking false-positive to active anti-HIV agent. J. Med. Chem., 2007, 50, 5324-5329.
79. Barreiro, G.; Guimarães, C.R.; Tubert-Brohman, I.; Lyons, T.M.; Tirado-Rives, J.; Jorgensen, W.L. Search for non-nucleoside inhibitors of HIV-1 reverse transcriptase using chemical similarity, molecular docking, and MM-GB/SA scoring. J. Chem. Inf. Model, 2007, 47, 2416-2428.
80. Jorgensen, W.L. Efficient Drug Lead Discovery and Optimization. Acc. Chem. Re., 2009, 42, 724-733.
81. Zeevaart, J.G.; Wang, L.; Thakur, V.V.; Leung, C.S.; Tirado-Rives, J.; Bailey, C.M.; Domaoal, R.A.; Anderson, K.S.; Jorgensen, W.L. Optimization of azoles as anti-human immunodeficiency virus agents guided by free-energy calculations. J. Am. Chem. Soc., 2008, 130, 9492-9499.
82. Leung, C.S., Zeevaart, J.G., Domaoal, R.A., Bollini, M., Thakur, V.V., Spasov, K.A., Anderson, K.S., Jorgensen, W.L. Eastern extension of azoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase; cyano group alternatives. Bioorg. Med. Chem. Lett., 2010, 20, 2485-2488.