Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics

Journal of Medicinal Chemistry

Volumn 42, Issue 7, 1999, Pages 1203-1212

  Dragovich, Peter S ^a   Prins, Thomas J ^a   Zhou, Ru ^a   Fuhrman, Shella A ^a   Patick, Amy K ^a   Matthews, David A ^a   Ford, Clifford E ^a   Meador III, James W ^a   Ferre, Rose Ann ^a   Worland, Stephen T ^a  

^a AGOURON PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYSTEINE; ENZYME; PROTEINASE INHIBITOR;

ANTIVIRAL ACTIVITY; ARTICLE; DRUG DESIGN; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN RHINOVIRUS; STRUCTURE ACTIVITY RELATION;

ANTIVIRAL AGENTS; CELL LINE; CYSTEINE ENDOPEPTIDASES; CYSTEINE PROTEINASE INHIBITORS; DIPEPTIDES; DRUG DESIGN; HUMANS; KETONES; MOLECULAR MIMICRY; RHINOVIRUS; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL PROTEINS;

EID: 0033535579     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm980537b     Document Type: Article

References (51)

1. (a) Couch, B. B. In Fields Virology, 3rd ed.; Fields, B. N., Knipe, D. M., Howley, P. M., et al., Eds.; Lippincott-Raven Publishers: Philadelphia, 1996; Vol. 1, Chapter 23, pp 713-734.
2. (b) McKinlay, M. A.; Pevear, D. C.; Rossmann, M. G. Annu. Rev. Microbiol. 1992, 46, 635.
3. (c) Phillpotts, R. J.; Tyrrell, D. A. J. Br. Med. Bull. 1985, 41, 386.
4. (d) Gwaltney, J. M. In Principles and Practices of Infectious Diseases; Mandell, G. L., Douglas, R. G., Bennett, J. E., Eds.; John Wiley & Sons: New York, 1985; Chapter 38, pp 351-355.
5. (e) Gwaltney, J. M. In Viral Infections of Humans; Evans, A. S., Ed.; Plenum Publishing Corp.: New York, 1982; Chapter 20, pp 491-517.
6. (a) Rueckert, R. R. In Fields Virology, 3rd ed.; Fields, B. N., Knipe, D. M., Howley, P. M., et al., Eds.; Lippincott-Raven Publishers: Philadelphia, 1996; Vol. 1, Chapter 21, pp 609-654.
7. (b) Kräusslich, H.-G.; Wimmer, E. Annu. Rev. Biochem. 1988, 57, 701.
8. Dragovich, P. S.; Webber, S. E.; Babine, R. E.; Fuhrman, S. A.; Patick, A. K.; Matthews, D. A.; Lee, C. A.; Reich, S. R.; Prins, T. J.; Marakovits, J. T.; Littlefield, E. S.; Zhou, R.; Tikhe, J.; Ford, C. E.; Wallace, M. B.; Meador, J. W., III; Ferre, R. A.; Brown, E. L.; Binford, S. L.; Harr, J. E. V.; DeLisle, D. M.; Worland, S. T. Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 1. Michael Acceptor Structure-Activity Studies. J. Med. Chem. 1998, 41, 2806-2818.
9. Dragovich, P. S.; Webber, S. E.; Babine, R. E.; Fuhrman, S. A.; Patick, A. K.; Matthews, D. A.; Reich, S. H.; Marakovits, J. T.; Prins, T. J.; Zhou, R.; Tikhe, J.; Littlefield, E. S.; Bleckman, T. M.; Wallace, M. B.; Little, T. L.; Ford, C. E.; Meador, J. W., III; Ferre, R. A.; Brown, E. L.; Binford, S. L.; DeLisle, D. M.; Worland, S. T. Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 2. Peptide Structure-Activity Studies. J. Med. Chem. 1998, 41, 2819-2834.
10. (a) Cordingley, M. G.; Callahan, P. L.; Sardana, V. V.; Garsky, V. M.; Colonno, R. J. Substrate Requirements of Human Rhinovirus 3C Protease for Peptide Cleavage in Vitro. J. Biol. Chem. 1990, 265, 9062-9065.
11. (b) Orr, D. C.; Long, A. C.; Kay, J.; Dunn, B. M.; Cameron, J. M. Hydrolysis of a Series of Synthetic Peptide Substrates by the Human Rhinovirus 14 3C Proteinase, Cloned and Expressed in Escherichia coli. J. Gen. Virol. 1989, 70, 2931-2942.
12. Cordingley, M. G.; Register, R. B.; Callahan, P. L.; Garsky, V. M.; Colonno, R. J. Cleavage of Small Peptides In Vitro by Human Rhinovirus 14 3C Protease Expressed in Escherichia coli. J. Virol. 1989, 63, 5037-5045.
13. 2′, etc.) is described in the following: Schlechter, I.; Berger, A. On the Size of the Active Site in Proteases. I. Papain. Biochem. Biophys. Res. Commun. 1967, 27, 157-162.
14. A similar series of HRV 3CP inhibitors has also recently been described. See: Kong, J.-s.; Venkatraman, S.; Furness, K.; Nimkar, S.; Shepherd, T. A.; Wang, Q. M.; Aubé, J.; Hanzlik, R. P. Synthesis and Evaluation of Peptidyl Michael Acceptors That Inactivate Human Rhinovirus 3C Protease and Inhibit Virus Replication. J. Med. Chem. 1998, 41, 2579-2587.
15. For other examples of Michael acceptor-containing cysteine protease inhibitors, see: (a) Roush, W. R.; Gwaltney, S. L., II; Cheng, J.; Scheidt, K. A.; McKerrow, J. H.; Hansell, E. Vinyl Sulfonate Esters and Vinyl Sulfonamides: Potent, Irreversible Inhibitors of Cysteine Proteases. J. Am. Chem, Soc. 1998, 120, 10994-10995.
16. (b) McGrath, M. E.; Klaus, J. L.; Barnes, M. G.; Brömme, D. Crystal Structure of Human Cathepsin K Complexed With a Potent Inhibitor. Nature Struct. Biol. 1997, 4, 105-109.
17. (c) Brömme, D.; Klaus, J. L.; Okamoto, K.; Rasnick, D.; Palmer, J. T. Peptidyl Vinyl Sulphones: A New Class of Potent and Selective Cysteine Protease Inhibitors. Biochem. J. 1996, 315, 85-89.
18. (d) Palmer, J. T.; Rasnick, D.; Klaus, J. L.; Brömme, D. Vinyl Sulfones as Mechanism-Based Cysteine Protease Inhibitors. J. Med. Chem. 1995, 38, 3193-3196.
19. (e) Liu, S.; Hanzlik, R. P. Structure-Activity Relationships for Inhibition of Papain by Peptide Michael Acceptors. J. Med. Chem. 1992, 35, 1067-1075.
20. (f) Hanzlik, R. P.; Thompson, S. A. Vinylogous Amino Acid Esters: A New Class of Inactivators for Thiol Proteases. J. Med. Chem. 1984, 27, 711-712.
21. For recent reviews of peptidomimetics, see: (a) Giannis, A.; Kolter, T. Peptidomimetics for Receptor Ligands-Discovery, Development, and Medical Perspectives. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244-1267.
22. (b) Gante, J. Peptidomimetics-Tailored Enzyme Inhibitors. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699-1720.
23. For selected examples, see: (a) Almquist, R. G.; Crase, J.; Jennings-White, C.; Meyer, R. F.; Hoefle, M. L.; Smith, R. D.; Essenburg, A. D.; Kaplan, H. R. Derivatives of the Potent Angiotensin Converting Enzyme Inhibitor 5(S)-Benzamido-4-oxo-6-phenylhexanoyl-L-proline: Effect of Changes at Positions 2 and 5 of the Hexanoic Acid Portion. J. Med. Chem. 1982, 25, 1292-1299.
24. (b) Holladay, M. W.; Salituro, F. G.; Rich, D. H. Synthetic and Enzyme Inhibition Studies of Pepstatin Analogues Containing Hydroxyethylene and Ketomethylene Dipeptide Isosteres. J. Med. Chem. 1987, 30, 374-383.
25. (c) Almquist, R. G.; Chao, W.-R.; Judd, A. K.; Mitoma, C.; Rossi, D. J.; Panasevich, R. E.; Matthews, R. J. Synthesis and Biological Activity of Ketomethylene-Containing Nonapeptide Analogues of Snake Venom Angiotensin Converting Enzyme Inhibitors. J. Med. Chem. 1988, 31, 561-567.
26. Harbeson, S. L.; Rich, D. H. Inhibition of Aminopeptidases by Peptides Containing Ketomethylene and Hydroxyethylene Amide Bond Replacements. J. Med. Chem. 1989, 32, 1378-1392.
27. Matthews, D. A.; Smith, W. W.; Ferre, R. A.; Condon, B.; Budahazi, G.; Sisson, W.; Villafranca, J. E.; Janson, C. A.; McElroy, H. E.; Gribskov, C. L.; Worland, S. Structure of Human Rhinovirus 3C Protease Reveals a Trypsin-like Polypeptide Fold, RNA-Binding Site, and Means for Cleaving Precursor Polyprotein. Cell 1994, 77, 761-771.
28. (a) Conradi, R. A.; Hilgers, A. R.; Ho, N. F. H.; Burton, P. S. The Influence of Peptide Structure on Transport Across Caco-2 Cells. Pharm. Res. 1991, 8, 1453-1460.
29. (b) Conradi, R. A.; Hilgers, A. R.; Ho, N. F. H.; Burton, P. S. The Influence of Peptide Structure on Transport Across Caco-2 Cells. II. Peptide Bond Modification Which Results in Improved Permeability. Pharm. Res. 1992, 9, 435-439.
30. (c) Burton, P. S.; Conradi, R. A.; Hilgers, A. R.; Ho, N. F. H.; Maggiora, L. L. The Relationship Between Peptide Structure and Transport Across Epithelial Cell Monolayers. J. Control. Release 1992, 19, 87-97.
31. (d) Kim, D.-C.; Burton, P. S.; Borchardt, R. T. A Correlation Between the Permeability Characteristics of a Series of Peptides Using an in Vitro Cell Culture Model (Caco-2) and Those Using an in Situ Perfused Rat Ileum Model of the Intestinal Mucosa. Pharm. Res. 1993, 10, 1710-1714.
32. 50 values.
33. The antirhinoviral properties of certain 3CP inhibitors were determined under similar conditions against several additional HRV serotypes in cell culture. In general, the activity observed for a given compound vs serotypes 1A, 2, and 10 was representative of its broad-spectrum antiviral properties. Serotype 14 nearly always proved to be the most susceptible to the antiviral agents under study. Full details of these experiments will be presented elsewhere (Patick, A. K Manuscript in preparation).
34. Dragovich, P. S.; Zhou, R.; Skalitzky, D. J.; Fuhrman, S. A.; Patick, A. K.; Ford, C. E.; Meador, J. W., III; Worland, S. T. Solid-Phase Synthesis of Irreversible Human Rhinovirus 3C Protease Inhibitors. 1. Optimization of Tripeptides Incorporating N-Terminal Amides. Bioorg. Med. Chem., in press.
35. 1 Lactam Moieties as L-Glutamine Replacements. J. Med. Chem. 1999, 42, 1213-1224.
36. (a) Dragovich, P. S.; Prins, T. J.; Zhou, H. Formal, Stereoselective Synthesis of Hydroxyethylene Dipeptide Isosteres Utilizing Pseudoephedrine Amides. J. Org. Chem. 1997, 62, 7872-7876.
37. (b) Bradbury, R. H.; Major, J. S.; Oldham, A. A.; Rivett, J. E.; Roberts, D. A.; Slater, A. M.; Timms, D.; Waterson, D. 1,2,4-Triazolo[4,3-α]pyrazine Derivatives with Human Renin Inhibitory Activity. 2. Synthesis, Biological Properties and Molecular Modeling of Hydroxyethylene Isostere Derivatives. J. Med. Chem. 1990, 33, 2335-2342.
38. (c) Herold, P.; Duthaler, R.; Rihs, G.; Angst, C. A Versatile and Stereocontrolled Synthesis of Hydroxyethylene Dipeptide Isosteres. J. Org. Chem. 1989, 54, 1178-1185.
39. Kaga, H.; Goto, K.; Takahashi, T.; Hino, M.; Tokuhashi, T.; Onto, K. A General and Stereoselective Synthesis of the Capsaicinoids via the Orthoester Claisen Rearrangement. Tetrahedron 1996, 52, 8451-8470.
40. For an alternate preparation of acid chloride 19, see: Gannett, P. M.; Nagel, D. L.; Reilly, P. J.; Lawson, T.; Sharpe, J.; Toth, B. The Capsaicinoids: Their Separation, Synthesis, and Mutagenicity. J. Org. Chem. 1988, 53, 1064-1071.
41. Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. Pseudoephedrine as a Practical Chiral Auxiliary for the Synthesis of Highly Enantiomerically Enriched Carboxylic Acids, Alcohols, Aldehydes, and Ketones. J. Am. Chem. Soc. 1997, 119, 6496-6511.
42. 17a,20 and the absence of significant amounts of diastereomerg of coupling product 27.
43. -, TPAP: A Catalytic Oxidant for Organic Synthesis. Synthesis 1994, 639-666.
44. Cyclopentyl chlorothiolformate was prepared in a manner similar to that described in: Eden, J. M.; Higginbottom, M.; Hill, D. R.; Horwell, D. C.; Hunter, J. C.; Martin, K; Pritchard, M. C,; Rahman, S. S.; Richardson, R. S.; Roberts, E. Rationally Designed "Dipeptoid" Analogues of Cholecystokinin (CCK): AT-Terminal Structure-Affinity Relationships of α-Methyl-Tryptophan Derivatives. Eur. J. Med. Chem. 1998, 28, 37-45. The benzyl chlorothiolformate used to prepare compounds 3 and 4 was also synthesized by this method.
45. Triisopropylsilane could typically be omitted from the deprotection reactions without adversely affecting the product yields.
46. (a) Askin, D.; Wallace, M. A.; Vacca, J. P.; Reamer, R. A.; Volante, R. P.; Shinkai, I. Highly Diastereoselective Alkylations of Chiral Amide Enolates: New Routes to Hydroxyethylene Dipeptide Isostere Inhibitors of HIV-1 Protease. J. Org. Chem. 1992, 57, 2771-2773.
47. (b) McWilliams, J. C.; Armstrong, J. D., III; Zheng, N.; Bhupathy, M.; Volante, R. P.; Reider, P. J. Tandem Asymmetric Transformations: An Asymmetric 1,2-Migration from a Higher Order Zincate Coupled with a Stereoselective Homoaldol Reaction. J. Am. Chem. Soc. 1996, 118, 11970-11971.
48. Luly, J. R.; Dellaria, J. F.; Plattner, J. J.; Soderquist, J. L.; Yi, N. A Synthesis of Protected Aminoalkyl Epoxides from α-Amino Acids. J. Org. Chem. 1987, 52, 1487-1492.
49. Hoffman, R. V.; Tao, J. A Simple, Stereoselective Synthesis of Ketomethylene Dipeptide Isosteres. Tetrahedron 1997, 53, 7119-7126.
50. The basic hydrolysis utilized to prepare γ-keto-acid 40 did not result in substantial epimerization as evidenced by the lack of significant diastereomers of the subsequent coupling product (41). However, considerable epimerization was noted when similar hydrolyses were attempted on other less-hindered γ-ketoester substrates (e.g., the Val-Phe isostere corresponding to γ-keto-ester 39).
51. Compound 15 was synthesized by a method analogous to that reported previously for the preparation of tripeptide-derived, irreversible 3CP inhibitors. See refs 3 and 4 above.