Inhibitors of MMP-1: An examination of P1' Cα gem-disubstitution in the N-carboxylalkylamine and glutaramide carboxylate series

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 14, 1996, Pages 1725-1730

  Robinson, Ralph P ^a   Cronin, Brian J ^a   Donahue, Kathleen M ^a   Jones, Brian P ^a   Lopresti Morrow, Lori L ^a   Mitchell, Peter G ^a   Rizzi, James P ^a   Reeves, Lisa M ^a   Yocum, Sue A ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ENZYME INHIBITOR; GLUTARAMIC ACID DERIVATIVE; METALLOPROTEINASE; METALLOPROTEINASE INHIBITOR;

ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; STRUCTURE ACTIVITY RELATION;

EID: 0030598671     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00304-6     Document Type: Article

References (15)

1. 1) For recent reviews on matrix metalloproteinases and their inhibitors, see: (a) Morphy, J, R.; Millican, T. A.; Porter, J. R Current Med. Chem. 1995, 2, 743.
2. (b) Beckett, R. P.; Davidson, A. H.; Drummond, A. H.; Huxley, P.; Whittaker, M. Drug Discovery Today, 1996, 1, 16.
3. 2) Brown, F. K.; Brown, P. J.; Bickett, D. M.; Chambers, C. L.; Davies, H. G.; Deaton, D. N.; Drewry, D.; Foley, M.; McElroy, A. B.; Gregson, M.; McGeehan, G. M.; Myers, P. L.; Norton, D.; Salovich, J. M.; Schoenen, F. J.; Ward, P. J. Med. Chem., 1994, 37, 674.
4. 3) Dickens, J. P.; Donald, D. K.; Kneen, G.; McCay, W. R. U.S. Patent 4,599,361.
5. 4) Lopez-Anaya, A. unpublished results.
6. 2 in a series of N-carboxyalkyl dipeptide inhibitors of MMP-3 has recently been reported to improve oral activity : Chapman, K. T.; Durette, P. L.; Caldwell, C. G.; Sperow, K. M.; Niedzwiecki, L. M.; Harrison, R. K.; Saphos, C.; Christen, A. J.; Olszewski, J. M.; Moore, V. L.; MacCoss; M.; Hagmann, W. K. Biorg. Med. Chem. Lett. 1996, 6, 803.
7. 2 were key structural modifications of an N-carboxyalkylamine leading to the discovery of candoxatril, an orally active prodrug of the NEP inhibitor candoxatrilat: (a) James, K.; Alabaster, C. T.; Barclay, P. L.; Barnish, I. T.; Blackburn, K. J.; Brown, D.; Campbell, S. F.; Cussans, N. J.; Danilewicz, J. C.; Palmer, M. J.; Terrett, N. K.; Samuels, G. M. R.; Wythes, M. J. Perspect. Med. Chem. 1993, 45.
8. (b) Danilewicz, J. C.; Barclay, P. L.; Barnish, I. T.; Brown, D.; Campbell, S. F.; James, K.; Samuels, G. M. R.; Terrett, N. K.; Wythes, M. J. Biochem. Biophys. Res. Comm. 1989, 164, 58.
9. 7) Robinson, R. P.; Ragan, J. A.; Cronin, B. J.; Donahue, K. M.; Lopresti-Morrow, L. L.; Mitchell, P. G.; Reeves, L. M.; Yocum, S. A. preceding paper in this issue.
10. 8) Lovejoy, B.; Cleasby, A.; Hassell, A. M.; Longley, K.; Luther, M. A.; Weigl, D.; McGeehan, G.; McElroy, A. B.; Drewry, D.; Lambert, M. H.; Jordan, S. R. Science 1994, 263, 375.
11. 2O/dioxane/ 25°); 3) Mannich reaction of the mono-acid with paraformaldehyde and piperidine (pyridine/70°); see Stetter,. H.; Kuhlmann, H. Synthesis 1979, 30.
12. 2 was generally associated with a modest loss of potency in a series of glutaramide-based inhibitors of MMP-3 (ref. 5).
13. 11) (a) Holland, D. R.; Barclay, P. L.; Danilewicz, J. C.; Matthews, B. W.; James, K. Biochemistry 1994, 33, 51.
14. (b) Morgan, B. P.; Scholtz, J. M.; Ballinger, M. D.; Zipkin, I. D.; Bartlett, P. A. J. Am. Chem. Soc. 1991, 113, 297.
15. 12) Enzyme assay: Recombinant full-length MMP-1 was activated with trypsin and assayed using a quenched fluorescent peptide substrate: Bickett, D. M.; Green, M. D.; Berman, J.; Dezube, M.; Howe, A. S.; Brown, P. J.; Roth, J. T.; McGeehan, G. M. Anal. Biochem. 1993, 212, 58.