Cycloalkylpyranones and cycloalkyldihydropyrones as HIV protease inhibitors: Exploring the impact of ring size on structure-activity relationships

Journal of Medicinal Chemistry

Volumn 39, Issue 20, 1996, Pages 4125-4130

  Romines, Karen R ^a   Morris, Jeanette K ^a   Howe, W Jeffrey ^b   Tomich, Paul K ^a   Horng, Miao Miao ^a   Chong, Kong Teck ^a   Hinshaw, Roger R ^a   Anderson, David J ^a   Strohbach, Joseph W ^a   Turner, Steve R ^a   Mizsak, Steve A ^a  

^a PFIZER INC   (United States)

^b NONE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

PROTEINASE; PROTEINASE INHIBITOR; PYRONE DERIVATIVE;

ANTIVIRAL ACTIVITY; ARTICLE; BINDING AFFINITY; CONTROLLED STUDY; DRUG CONFORMATION; DRUG POTENCY; ENERGY; ENZYME INHIBITION; HUMAN; HUMAN CELL; STRUCTURE ACTIVITY RELATION;

ANTI-HIV AGENTS; ASPARTIC ENDOPEPTIDASES; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; CYCLIZATION; HIV PROTEASE INHIBITORS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN CONFORMATION; PYRONES; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 10144232120     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960296c     Document Type: Article

References (22)

1. (a) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 17, 133-144.
2. (b) Redshaw, S. Inhibitors of HIV Proteinase. Exp. Opin. Invest. Drugs 1994, 3, 273-286.
3. 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 Design of HIV Protease Inhibitors: 4-Hydroxycoumarins and 4-Hydroxy-2-pyrones as Non-peptidic Inhibitors. J. Med. Chem. 1994, 37, 3200-3204.
4. For a review of the 4-hydroxycoumarins and related 4-hydroxypyrone templates, see: Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptidic HIV Protease Inhibitors. Current Med. Chem. 1995, 2, 825-838 and references cited therein.
5. 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.
6. 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.
7. (a) 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. J. Med. Chem. 1995, 38, 4968-4971.
8. (b) Skulnick, H. I.; Johnson, P. D.; Aristoff, P. A.; Morris, J. K.; Lovasz, K. D.; Howe, W. J.; Watenpaugh, K. D.; Janakiraman, M. N.; Anderson, D. J.; Reischer, R. J.; Schwartz, T. M.; Banitt, L. S.; Tomich, P. K.; Lynn, J. C.; Horng, M.-M.; Chong, K.-T.; Hinshaw, R. R.; Dolak, L. A.; Seest, E. P.; Schwende, F. J.; Rush, B. D.; Howard, G. M.; Toth, L. N.; Wilkinson, K. R.; Kakuk, T. J.; Johnson, C. W.; Cole, S. L.; Zaya, R. M.; Zipp, G. L.; Possert, P. L.; Dalga, R. J.; Romines, K. R. Structure-Based Design of Nonpeptidic HIV Protease Inhibitors: The Sulfonamide-Substituted Cyclooctylpyranones. J. Med. Chem., submitted.
9. J. W. Strohbach, S. R. Turner, and S. Thaisrivongs. Unpublished Results.
10. 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. Chem. Ber. 1986, 119, 3394-3404.
11. i values.
12. The dramatic increase in binding affinity of the meta sulfonamide substituted derivatives is presumably due to the ability of the sulfonamide aryl substituent, in this case the 4-cyano-2-pyridyl group, to efficiently interact with the S3′ pocket of the protease. In addition, X-ray crystal structures of similar compounds have shown that the aryl group occupying the S3′ region is able to form π-stacking interactions with the Arg 8 residue of the enzyme. See ref 6.
13. These synthetic procedures were adapted from routes developed for related templates. Romero, D. L.; Tommasi, R. A.; Janakiraman, M. N.; Strohbach, J. W.; Turner, S. R.; Biles, C.; Morge, R. A.; Johnson, P. D.; Aristoff, P. A.; Tomich, P. K.; Lynn, J. C.; Horng, M-M.; Chong, K-T.; Hinshaw, R. R.; Howe, W. J.; Finzel, B. C.; Watenpaugh, K. D.; Thaisrivongs, S. J. Med. Chem., submitted.
14. In vitro enzyme kinetics for these compounds were performed as described in ref 2.
15. 14 using the Amber * united atom forcefield, the PRCG minimizer, and the surface area solvation approximation, as implemented in BatchMin. A model of each compound was constructed in the HIV-2 protease binding site, starting from the X-ray crystal structure of the complex of 2c. Each model was then subjected to 1000 steps of torsional variation of the cycloalkyl ring bonds, followed by energy minimization of the ligand within the field of an 8 Å nonmoving shell of protein atoms, to arrive at an energy-ordered list of "bound" conformations for each ligand. The ligand model was then moved away from the protein and the procedure was repeated. The nonmoving shell of protein atoms contributed a solvation component to the overall "unbound" energies, even though it did not contribute an interaction energy with the ligand. The difference between the lowest bound and unbound energies became the approximate binding energy for that compound. The entire procedure was repeated, using the X-ray structure of the complex of 2d as the source of protein atom positions. The binding energies calculated in the two runs were then averaged.
16. 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.
17. 3Al. For the synthesis of this reagent, see: Jubert, C.; Knochel, P. Preparation of Polyfunctional Nitro Olefins and Nitroalkanes Using the Copper-Zinc Reagents RCu(CN)ZnI. J. Org. Chem. 1992, 57, 5431-5438.
18. 6b,7 It suggests that there is an additional component in the binding interaction between the S3′ region of the enzyme and the pyridyl sulfonamide substituent relative to the phenyl sulfonamide substituents, but the specific nature of such interactions is unknown at this time.
19. Antiviral activity was measured as described in Chong, K.-T.; Pagano, P. J.; Hinshaw, R. R. Bisheteroarylpiperazine Reverse Transcriptase Inhibitor in Combination with 3′-Azido-3′-Deoxythymidine or 2′,3′-Dideoxycytidine Synergistically Inhibits Human Immunodeficiency Virus Type 1 Replication In Vitro. Antimicrob. Agents Chemother. 1994, 38, 288-293.
20. i values, into antiviral activity in cell culture cannot be directly correlated to any single factor, such as protein binding, cell membrane permeability, or solubility, just to name a few. This issue continues to be an area of ongoing research.
21. Prepared using the procedure of Roblin and Clapp: Roblin, R. O.; Clapp, J. W. J. Am. Chem. Soc. 1950, 72, 4890-4892.
22. Forrest, H. S.; Walker, J. Chemotherapeutic Agents of the Sulphone Type. Part V. 2:5-Disubstituted Derivatives of Pyridine. The Preparation of Heterocyclic Sulfonamides. J. Chem. Soc. 1948, 1939-1945.