Design of annulated pyrazoles as inhibitors of HIV-1 reverse transcriptase

Journal of Medicinal Chemistry

Volumn 51, Issue 23, 2008, Pages 7449-7458

  Sweeney, Zachary K ^a   Harris, Seth F ^a   Arora, Nidhi ^a   Javanbakht, Hassan ^a   Li, Yu ^a   Fretland, Jennifer ^a   Davidson, James P ^a   Billedeau, J Roland ^a   Gleason, Shelley K ^a   Hirschfeld, Donald ^a   Kennedy Smith, Joshua J ^a   Mirzadegan, Taraneh ^a   Roetz, Ralf ^a   Smith, Mark ^a   Sperry, Sarah ^a   Suh, Judy M ^a   Wu, Jeffrey ^a   Tsing, Stan ^a   Villaseñor, Armando G ^a   Paul, Amber ^a   Su, Guoping ^a   Heilek, Gabrielle ^a   Hang, Julie Q ^a   Zhou, Amy S ^a   Jernelius, Jesper A ^a   Zang, Fang Jie ^a   Klumpp, Klaus ^a   more..

^a ROCHE BIOSCIENCE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 CHLORO 5 [6 CHLORO 2 FLUORO 3 (1H PYRAZOLO[3,4 C]PYRIDAZIN 3 YLMETHYL)PHENOXY]BENZONITRILE; DELAVIRDINE; EFAVIRENZ; ETRAVIRINE; PYRAZOLE DERIVATIVE; PYRAZOLO[3,4 C]PYRIDAZINE DERIVATIVE; RNA DIRECTED DNA POLYMERASE; RNA DIRECTED DNA POLYMERASE INHIBITOR; TROVIRDINE; UNCLASSIFIED DRUG;

ANNULATION REACTION; ARTICLE; BINDING AFFINITY; DRUG DESIGN; DRUG EFFICACY; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LIGAND BINDING; MOLECULAR INTERACTION; MOLECULAR STABILITY; NONHUMAN; POINT MUTATION; PROTEIN CONFORMATION; STRUCTURE ACTIVITY RELATION; VIRUS INHIBITION; VIRUS REPLICATION; WILD TYPE;

ANIMALS; ANTI-HIV AGENTS; BINDING SITES; CELL LINE, TRANSFORMED; CRYSTALLOGRAPHY, X-RAY; DOGS; DRUG DESIGN; HAPLORHINI; HIV REVERSE TRANSCRIPTASE; HIV-1; HUMANS; HYDROGEN BONDING; MICROBIAL SENSITIVITY TESTS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PYRAZOLES; RATS; REVERSE TRANSCRIPTASE INHIBITORS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 57349096037     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm800527x     Document Type: Article

References (37)

1. Zhou, Z.; Lin, X.; Madura, J. D. HIV-1 RT nonnucleoside inhibitors and their interaction with RT for antiviral drug development. Infect. Disord.: Drug Targets 2006, 6, 391-413.
2. Zhang, Z.; Hamatake, R.; Hong, Z. Clinical utility of current NNRTIs and perspectives of new agents in this class under development. Antiviral Chem. Chemother. 2004, 15, 121-134.
3. Basavapathruni, A.; Anderson, K. S. Reverse transcription of the HIV-1 pandemic. FASEB J. 2007, 21, 3795-3808.
4. Boone, L. Next-generation HIV-1 non-nucleoside reverse transcriptase inhibitors. Curr. Opin. Invest. Drugs 2006, 7, 128-135.
5. Balzarini, J. Current status of the non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1. Curr. Top. Med. Chem. 2004, 4, 921-944.
6. Sweeney, Z. K.; Klumpp, K. Improving non-nucleoside reverse transcriptase inhibitors for first-line treatment of HIV infection: the development pipeline and recent clinical data. Curr. Opin. Drug Discovery Dev. 2008, 11, 458-470.
7. Xia, Q.; Radzio, J.; erson, K.; Slurs, C. Probing nonnucleoside inhibitor-induced active-site distortion in HIV-1 reverse transcriptase by transient kinetic analyses. Protein Sci. 2007, 16, 1728-1737.
8. Jorgensen, W. L.; Ruiz, C.; Tirado, R.; Basavapathruni, A.; Anderson, K. S.; Hamilton, A. D. Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett. 2006, 16, 663-667.
9. Zhou, Z.; Madrid, M.; Evanseck, J.; Madura, J. Effect of a bound non-nucleoside RT inhibitor on the dynamics of wild-type and mutant HIV-1 reverse transcriptase. J. Am. Chem. Soc. 2005, 127, 17253-17260.
10. Teague, S. J. Implications of protein flexibility for drug discovery. Nat. Rev. Drug Discovery 2003, 2, 527-541.
11. 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.
12. 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.
13. Ren, J.; Stammers, D. K. HIV reverse transcriptase structures: designing new inhibitors and understanding mechanisms of drug resistance. Trends Pharmacol. Sci. 2005, 26, 4-7.
14. 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. Structure 2000, 8, 1089-1094.
15. Das, K.; Clark, A. D., Jr.; Lewi, P. J.; Heeres, J.; de Jonge, M. R.; Koymans, L. M.; Vinkers, H. M.; Daeyaert, F.; Ludovici, D. W.; Kukla, M. J.; De, C. 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.; 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.
16. Cantrell, A. S.; Engelhardt, P.; Hogberg, M.; Jaskunas, S. R.; Johansson, N. G.; Jordan, C. L.; Kangasmetsa, J.; Kinnick, M. D.; Lind, P.; Morin, J. M., Jr.; Muesing, M. A.; Noreen, R.; Oberg, B.; Pranc, P.; Sahlberg, C.; Ternansky, R. J.; Vasileff, R. T.; Vrang, L.; West, S. J.; Zhang, H. Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure-activity relationship studies of PETT analogs. J. Med. Chem. 1996, 39, 4261-4274.
17. Romines, K.; Freeman, G.; Schaller, L.; Cowan, J.; Gonzales, S.; Tidwell, J.; Andrews, C.; Stammers, D.; Hazen, R.; Ferris, R.; Short, S.; Chan, J.; Boone, L. Structure-activity relationship studies of novel benzophenones leading to the discovery of a potent, next generation HIV nonnucleoside reverse transcriptase inhibitor. J. Med. Chem. 2006, 49, 727-739.
18. Girardet, J.-L.; Koh, Y.-H.; De La Rosa, M.; Gunic, E.; Zhang, Z.; Hamatake, R.; Yeh, L. The Discovery of RDEA806, a Potent New HIV NNRTI in Phase 1 Clinical Trials. Presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007; H-1040.
19. (a) Sweeney, Z. K.; Dunn, J. P.; Li, Y.; Heilek, G.; Dunten, P.; Elworthy, T. R.; Han, X.; Harris, S. F.; Hirschfeld, D. R.; Hogg, J. H.; Huber, W.; Kaiser, A. C.; Kertesz, D. J.; Kim, W.; Mirzadegan, T.; Roepel, M. G.; Saito, Y. D.; Silva, T. M.; Swallow, S.; Tracy, J. L.; Villasenor, A.; Vora, H.; Zhou, A. S.; Klumpp, K. Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett. 2008, 18, 4352-4354.
20. (b) Sweeney, Z. K.; Acharya, S.; Briggs, A.; Dunn, J. P.; Elworthy, T. R.; Fretland, J.; Giannetti, A. M.; Heilek, G.; Li, Y.; Kaiser, A. C.; Martin, M.; Saito, Y. D.; Smith, M.; Suh, J. M.; Swallow, S.; Wu, J.; Hang, J. Q.; Zhou, A. S.; Klumpp, K. Discovery of triazolinone non-nucleoside inhibitors of HIV reverse transcriptase. Bioorg. Med. Chem. Lett. 2008, 4348-4351.
21. Following the completion of this work, a closely related series of annulated pyrazoles was disclosed: Tucker, T. J.; Saggar, S.; Sisko, J. T.; Tynebor, R. M.; Felock, P. J.; Flynn, J. A.; Lai, M.-T.; Liang, Y.; Liu, M.; McGaughey, G.; Miller, M. D.; Moyer, G.; Munshi, V.; Poehnelt, R. A.; Prasad, S.; Sanchez, R.; Torrent, M.; Vacca, J. P.; Williams, T. M.; Wan, B.-L.; Yan, Y. The Design and Synthesis of Diaryl Ether Second Generation HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) with Enhanced Potency versus Key Clinical Mutations. Presented at the 235th National Meeting of the American Chemical Society, New Orleans, LA, 2008; MEDI-174.
22. Mager, P. P. Evidence of a butterfly-like configuration of structurally diverse allosteric inhibitors of the HIV-1 reverse transcriptase. Drug Des. Discovery 1996, 14, 241-257.
23. (a) Ren, J.; Chamberlain, P. P.; Stamp, A.; Short, S. A.; Weaver, K. L.; Romines, K. R.; Hazen, R.; Freeman, A.; Ferris, R. G.; rews, C. W.; Boone, L.; Chan, J. H.; Stammers, D. K. Structural basis for the improved drug resistance profile of new generation benzophenone non-nucleoside HIV-1 reverse transcriptase inhibitors. J. Med. Chem. 2008, 51, 5000-5008.
24. (b) Rodgers, D. W.; Gamblin, S. J.; Harris, B. A.; Ray, S.; Culp, J. S.; Hellmig, B.; Woolf, D. J.; Debouck, C.; Harrison, S. C. The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 1222-1226.
25. Huang, H.; Chopra, R.; Verdine, G. L.; Harrison, S. C. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 1998, 282, 1669-1675.
26. Paulini, R.; Muller, K.; Diederich, F. Orthogonal multipolar interactions in structural chemistry and biology. Angew. Chem., Int. Ed. 2005, 44, 1788-1805.
27. (a) Toth, G.; Bowers, S. G.; Truong, A. P.; Probst, G. The role and significance of unconventional hydrogen bonds in small molecule recognition by biological receptors of pharmaceutical relevance. Curr. Pharm. Des. 2007, 13, 3476-3493.
28. (b) Ren, J.; Nichols, C.; Bird, L. E.; Fujiwara, T.; Sugimoto, H.; Stuart, D. I.; Stammers, D. K. Binding of the second generation non-nucleoside inhibitor S-1153 to HIV-1 reverse transcriptase involves extensive main chain hydrogen bonding. J. Biol. Chem. 2000, 275, 14316-14320.
29. Das, K.; Lewi, P.; Hughes, S. H.; Arnold, E. Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors. Prog. Biophys. Mol. Biol. 2005, 88, 209-231.
30. Hopkins, A. L.; Ren, J.; Tanaka, H.; Baba, M.; Okamato, M.; Stuart, D. I.; Stammers, D. K. Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants. J. Med. Chem. 1999, 42, 4500-4505.
31. Das, K.; Bauman, J. D.; Clark, A. D.; Frenkel, Y. V.; Lewi, P. J.; Shatkin, A. J.; Hughes, S. H.; Arnold, E. High-resolution structures of HIV-1 reverse transcriptase/TMC-278 complexes: strategic flexibility explains potency against resistant mutations. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 1466-1471.
32. (a) Pauwels, R.; Balzarini, J.; Baba, M.; Snoeck, R.; Schols, D.; Herdewijn, P.; Desmyter, J.; De, C. E. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods 1988, 20, 309-321.
33. (b) Petropoulos, C. J.; Parkin, N. T.; Limoli, K. L.; Lie, Y. S.; Wrin, T.; Huang, W.; Tian, H.; Smith, D; Winslow, G. A.; Capon, D. J.; Whitcomb, J. M. A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 2000, 44, 920-928.
34. DeLano, W. L. The PyMOL Molecular Graphics System. http://www.pymol.org.
35. Emsley, P.; Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60, 2126-2132.
36. Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1997, 53, 240-255.
37. The CCP4 suite: programs for protein crystallography. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1994, 50, 760-763.