Inhibition of Stromelysin-1 (MMP-3) by P₁‘-Biphenylylethyl Carboxyalkyl Dipeptides

Craig K. Esser,* Robert L. Bugianesi, Charles G. Caldwell, Kevin T. Chapman, Philippe L. Durette, Narindar N. Girotra, Ihor E. Kopka, Thomas J. Lanza, Dorothy A. Levorse, Malcolm MacCoss, Karen A. Owens, Mitree M. Ponpipom, Joseph P. Simeone, Richard K. Harrison,^† Lisa Niedzwiecki,^† Joseph W. Becker, Alice I. Marcy, Melinda G. Axel, Amy J. Christen,^‡ Joseph McDonnell,^‡ Vernon L. Moore,^‡ Julie M. Olszewski,^‡ Cheryl Saphos,^‡ Denise M. Visco,^‡ Frank Shen, Adria Colletti,^§ Philip A. Krieter,^§ and William K. Hagmann

J. Med. Chem., 1997, 40 (6), pp 1026–1040

DOI: 10.1021/jm960465t

Publication Date (Web): March 14, 1997

Copyright © 1997 American Chemical Society

, , , , ,

Carboxyalkyl peptides containing a biphenylylethyl group at the P₁‘ position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10−50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P₁‘, a tert-butyl group at P₂‘, and a methyl group at P₃‘ produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P₁‘-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P₁‘ proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4‘-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentanedioic acid 1-(α(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a K_i of 10 nM against MMP-3 and an ED₅₀ of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1β injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED₅₀ = 6 mg/kg iv).