Structure-based design of nonpeptidic HIV protease inhibitors: The sulfonamide-substituted cyelooctylpyranones

Journal of Medicinal Chemistry

Volumn 40, Issue 7, 1997, Pages 1149-1164

  Skulnick, Harvey I ^a   Johnson, Paul D ^a   Aristoff, Paul A ^a   Morris, Jeanette K ^b   Lovasz, Kristine D ^b   Howe, W Jeffrey ^c   Watenpaugh, Keith D ^b   Janakiraman, Musiri N ^b   Anderson, David J ^a   Reischer, Robert J ^a   Schwartz, Theresa M ^a   Banitt, Lee S ^a   Tomich, Paul K ^d   Lynn, Janet C ^d   Horng, Miao Miao ^d   Chong, Kong Teck ^e   Hinshaw, Roger R ^e   Dolak, Lester A ^d   Seest, Eric P ^d   Schwende, Francis J ^f   Rush, Bob D ^f   Howard, Gina M ^f   Toth, Lisa N ^f   Wilkinson, Karen R ^f   Kakuk, Thomas J ^g   Johnson, Carol W ^g   Cole, Serena L ^g   Zaya, Renee M ^g   Zipp, Gail L ^h   Possert, Peggy L ^h   Dalga, Robert J ^h   Zhong, Wei Zhu ^f   Williams, Marta G ^f   Romines, Karen R ^b   more..

^a Medicinal Chemistry Research   (United States)

^b Structural   (United States)

^c Pharmacia and Upjohn   (United States)

^d Chemical and Biological Screening   (United States)

^e Infectious Diseases Research   (United States)

^f Drug Metabolism Research   (United States)

^g Pharmacia and Upjohn   (United States)

^h Pharmaceutical Development   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 CYANO N [3 [CYCLOPROPYL(5,6,7,8,9,10 HEXAHYDRO 4 HYDROXY 2 OXO 2H CYCLOOCTA[B]PYRAN 3 YL)METHYL]PHENYL]BENZENESULFONAMIDE; ANTIVIRUS AGENT; PROTEINASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; ARTICLE; BINDING AFFINITY; DOG; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG CONFORMATION; DRUG POTENCY; DRUG PROTEIN BINDING; ENZYME BINDING; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS; INTRAVENOUS DRUG ADMINISTRATION; MALE; NONHUMAN; ORAL DRUG ADMINISTRATION; PROTEINASE INHIBITION; RAT; STRUCTURE ACTIVITY RELATION; VIRUS INHIBITION;

ANIMALS; CELL LINE; CRYSTALLOGRAPHY, X-RAY; DOGS; HIV PROTEASE INHIBITORS; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MALE; MASS SPECTROMETRY; MODELS, MOLECULAR; PYRONES; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 13144269947     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960441m     Document Type: Article

References (39)

1. Laurence, J. AIDS Research: The Second Decade. AIDS Res. Hum. Retrov. 1994, 10, 1585-1589.
2. Aggleton, P.; O'Reilly, K; Slutkin, G.; Davies, P. Risking Everything? Risk Behavior, Behavior Change, and AIDS. Science 1994, 265, 341-345.
3. (a) Pillay, D.; Bryant, M.; Getman, D.; Richman, D. D. HIV-1 Protcase Inhibitors: Their Development, Mechanism of Action and Clinical Potential. Rev. Med. Virol. 1995, 5, 23-33.
4. (b) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-design methodologies. Trends Pharmacol. Sci. 1995, 16, 67-75.
5. Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1994, 25, 399-454.
6. (a) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 17, 133-144.
7. (b) Redshaw, S. Inhibitors of HIV Proteinase. Exp. Opin. Invest. Drugs 1994, 3, 273-286.
8. (a) Olson, G. L.; Bolin, D. R.; Bonner, M. P.; Bös, M.; Cook, C. M.; Fry, D. C.; Graves, B. J.; Hatada, M.; Hill, D. E.; Kahn, M.; Madison, V. S.; Rusiecki, V. K.; Sarabu, R.; Sepinwall, J.; Vincent, G. P.; Voss, M. E. Concepts and Progress in the Development of Peptide Mimetics. J. Med. Chem. 1993, 36, 3039-3049.
9. (b) Plattner, J. J.; Norbeck, D. W. Chapter 5. Obstacles to Drug Development from Peptide Leads. In Drug Discovery Technologies; Clark, C. R., Moos, W. H., Eds.; Ellis Horwood: Chichester, England, 1990; pp 92-126.
10. For recent examples, see: (a) Maligres, P. E.; Upadhyay, V.; Rossen, K.; Cianciosi, S. J.; Purick, R. M.; Eng, K. K.; Reamer, R. A.; Askin, D.; Volante, R. P.; Reider, P. J. Diastereoselective Syn-Epoxidation of 2-Alkyl-4-Enamides to Epoxyamides: Synthesis of the Merck HIV-1 Protease Inhibitor Epoxide Intermediate. Tetrahedron Lett. 1995, 36, 2195-2198.
11. (b) Parkes, K. E. B.; Bushnell, D. J.; Crackett, P. H.; Dunsdon, S. J.; Freeman, A. C.; Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.; Martin, J. A.; Merrett, J. H.; Redshaw, S.; Spurden, W. C.; Thomas, G. J. Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959. J. Org. Chem. 1994, 59, 3656-3664.
12. (c) Baker, W. R.; Condon, S. L. Dipeptide Isosteres. 1. Synthesis of Dihydroxyethylene Dipeptide Isosteres via Diastereoselective Additions of Alkyllithium Reagents to N,N-Dimethylhydrazones. Preparation of Renin and HIV-1 Protease Inhibitor Transition-State Mimics. J. Org. Chem. 1993, 58, 3277-3284.
13. Thaisrivongs, S.; Tomich, P. K.; Watenpaugh, K. D.; Chong, K.-T.; Howe, W. J.; Yang, C.-P.; Strohbach, J. W.; Turner, S. T.; McGrath, J. P.; Bohanon, M. J.; Lynn, J. C.; Mulichak, A. M.; Spinelli, P. A.; Hinshaw, R. R.; Pagano, P. J.; Moon, J. B.; Ruwart, M. J.; Wilkinson, K. F.; Rush, B. D.; Zipp, G. L.; Dalga, R. J.; Schwende, F. J.; Howard, G. M.; Padbury, G. E.; Toth, L. N.; Zhao, Z.; Koeplinger, K. A.; Kakuk, T. J.; Cole, S. L.; Zaya, R. M.; Piper, R. C.; Jeffrey, P. Structure-Based Designed of HIV Protease Inhibitors: 4-Hydroxycoumarins and 4-Hydroxy-2-pyrones as Non-peptidic Inhibitors. J. Med. Chem. 1994, 37, 3200-3204.
14. For a summary of structure-based drug design work using 1 and related 4-hydroxypyrone templates, see Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Non-peptidic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838 and references cited therein.
15. Romines, K. R.; Watenpaugh, K. D.; Tomich, P. K.; Howe, W. J.; Morris, J. K.; Lovasz, K. D.; Mulichak, A. M.; Finzel, B. C.; Lynn, J. C.; Horng, M. M.; Schwende, F. J.; Ruwart, M. J.; Zipp, G. L.; Chong, K.-T.; Dolak, L. A.; Toth, L. N.; Howard, G. M.; Rush, B. D.; Wilkinson, K. F.; Possert, P. L.; Dalga, R. J.; Hinshaw, R. R. Use of Medium-Sized Cycloalkyl Rings to Enhance Secondary Binding: Discovery of a New Class of HIV Protease Inhibitors. J. Med. Chem. 1995, 38, 1884-1891.
16. The nomenclature used here to describe the regions of the protease is that of Schechter, I.; Berger, A. On the Size of the Active Site in Proteases I. Papain. Biochem. Biophys. Res. Commun. 1967, 27, 157-162.
17. Thaisrivongs, S.; Watenpaugh, K. D.; Howe, W. J.; Tomich, P. K.; Dolak, L. A.; Chong, K.-T.; Tomich, C.-S. C.; Tomasselli, A. G.; Turner, S. R.; Strohbach, J. W.; Mulichak, A. M.; Janakiraman, M. N.; Moon, J. B.; Lynn, J. C.; Horng, M.-M.; Hinshaw, R. R.; Curry, K. A.; Rothrock, D. J. Structure-Based Design of Novel HIV Protease Inhibitors: Carboxamide-Containing 4-Hydroxycoumarins and 4-Hydroxy-2-pyrones as Potent Nonpeptidic Inhibitors. J. Med. Chem. 1995, 38, 3624-3637.
18. Romines, K. R.; Watenpaugh, K. D.; Howe, W. J.; Tomich, P. K.; Lovasz, K. D.; Morris, J. K.; Janakiraman, M. N.; Lynn, J. C.; Horng, M.-M.; Chong, K.-T.; Hinshaw, R. R.; Dolak, L. A. Structure-Based Design of Nonpeptidic HIV Protease Inhibitors from a Cyclooctylpyranone Lead Structure. J. Med. Chem. 1995, 38, 4463-4473.
19. Skulnick, H. I.; Johnson, P. D.; Howe, W. J.; Tomich, P. K.; Chong, K.-T.; Watenpaugh, K. D.; Janakiraman, M. N.; Dolak, L. A.; McGrath, J. P.; Lynn, J. C.; Horng, M.-M.; Hinshaw, R. R.; Zipp, G. L.; Ruwart, M. J.; Schwende, F. J.; Zhong, W.-Z.; Padbury, G. E.; Dalga, R. J.; Shiou, L.; Possert, P. L.; Rush, B. D.; Wilkinson, K. F.; Howard, G. M.; Toth, L. N.; Williams, M. G.; Kakuk, T. J.; Cole, S. L.; Zaya, R. M.; Lovasz, K. D.; Morris, J. K.; Romines, K. R.; Thaisrivongs, S.; Aristoff, P. A. Structure-Based Design of Sulfonamide-Substituted Non-Peptidic HIV Protease Inhibitors. J. Med. Chem. 1995, 38, 4968-4971.
20. i values, assays were incubated for 72 h at a lower enzyme concentration (0.2-0.5 nM). Otherwise the assay conditions were as described in ref 7.
21. In our previous communication (ref 13) we reported that the presence of the p-cyano substituent causes a shift of the sulfonamide which weakens the hydrogen-bonding interaction between the NH of the inhibitor and the Gly 48 residue. Further refinement of the HIV protease complexes with 8h and 51a indicates that this is not the case.
22. Thaisrivongs, S.; Janakiraman, M. N.; Chong, K.-T.; Tomich, P. K.; Dolak, L. A.; Turner, S. R.; Strohbach, J. W.; Lynn, J. C.; Horng, M.-M.; Hinshaw, R. R.; Watenpaugh, K. D. Structure-Based Design of Novel HIV Protease Inhibitors: Sulfonamide-Containing 4-Hydroxycoumarins and 4-Hydroxy-2-pyrones as potent Nonpeptidic Inhibitors. J. Med. Chem. 1996, 39, 2400-2410.
23. 50 = 0.03 μM).
24. The absolute stereochemistry of the enantiomers was determined via an asymmetric synthesis which will be reported elsewhere. R. B. Gammill, personal communication.
25. Chong, K.-T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124.
26. Experiments performed at SRA Technologies, Inc., Rockville, MD.
27. Our thanks to Dr. Alfredo G. Tomasselli for renin inhibition data and Professor Ben M. Dunn, University of Florida, Gainesville, for the remaining enzyme inhibition data.
28. Mosaic was developed at Pharmacia and Upjohn as an extension to the MacroModel/BatchMin software system developed at Columbia University. Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C.; MacroModel - An Integrated Software System for Modeling Organic and Bioorganic Molecules Using Molecular Mechanics. J. Comput. Chem. 1990, 11, 440-467.
29. Mildner, A. M.; Rothrock, D. J.; Leone, J. W.; Bannow, C. A.; Lull, J. M.; Reardon, I. M.; Sarcich, J. L.; Howe, W. J.; Tomich, C. C.; Smith, C. W.; Heinrikson, R. L.; Tomasselli, A. G. The HIV-1 Protease as Enzyme and Substrate: Mutagenesis of Autolysis Sites and Generation of a Stable Mutant with Retained Kinetic Properties. Biochemistry 1994, 33, 9405-9413.
30. Howard, A. J.; Gilliland, G. L.; Finzel, B. C.; Poulos, T. L.; Olendorf, D. H.; Salemme, F. R. The Use of an Imaging Proportional Counter in Macromolecular Crystallography. J. Appl. Crystallogr. 1987, 20, 383-387.
31. Watenpaugh, K. D. Conformational Energy as a Restraint in Refinement. In Proceeding of the Molecular dynamics Workshop 1984, Chapel Hill; Hermans, J., Ed.; Polycrystal Book: Western Springs, IL, 1985; pp 77-80.
32. Jones, T. A. Interactive Computer Graphics: FRODO. Methods Enzymol. 1985, 115, 157-171.
33. Sack, J. S. CHAIN: A Crystallographic Modeling Program. J Mol. Graphics 1988, 6, 224-225.
34. Xtal 3.0 Reference Manual; Hall, S. R., Stewart, J. M., Eds.; Universities of Western Australia, Perth and Maryland: College Park, MD, 1990.
35. Bernstein, F. C.; Koetzle, T. F.; Williams, G. J. B.; Meyer, E. F.; Brice, M. D.; Rogers, J. B.; Kennard, O.; Shimanouchi, T.; Tasumi, M. The Protein Data Bank: A Computer-based Archival File for Macromolecular Structures. J. Mol. Biol. 1977, 112, 535-542.
36. Effenberger, F.; Ziegler, T.; Schönwälder, K.-H.; Kesmarszky, T.; Bauer, B. Die Acylierung von (Trimethylsilyl)enolethern mit Malonyldichlorid - Darstellung von 4-Hydroxy-2H-pyran-2-onen. (Acylation of trimethylsilyl enol ethers with malonyl dichloride - Synthesis of 4-hydroxy-2H-pyran-2-ones.) Chem. Ber. 1986, 119, 3394-3404.
37. Sauer, E.; Bendig J.; Hentzenroder, K. Synthese von Di- und Triazidoverbindungen durch Veresterung von p-Azidobenensulfochlorid. (Synthesis of di- and triazidocompounds through esterification of 4-azidobenzene sulfonyl chloride.) J. Prakt. Chem. 1988, 330, 492.
38. Erlenmeyer, H.; Kiefer, H. Zur Kenntnis der Thiazol-4-sulfonsäure und der Thiazol-5-sulfonsäure. (Characterization of thiazole-4-sulfonic acid and thiazole-5-sulfonic acid.) Helv. Chim. Acta 1945, 28, 985-991.
39. Romines, K. R.; Morris, J. K., Howe, W. J.; Tomich, P. K.; Horng, M.-M.; Chong, K.-T.; Hinshaw, R. R.; Anderson, D. J.; Strohbach, J. W.; Turner, S. R.; Mizsak, S. A. Cycloalkylpyranones and Cycloalkyldihydropyrones as HIV Protease Inhibitors: Exploring the Impact of Ring Size on SAR. J. Med. Chem. 1996, 39, 4125-4130.