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

Abstract

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-pentane dioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a Ki 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-1 beta 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).

Differential expression of cathepsins B and L compared with matrix metalloproteinases and their respective inhibitors in rheumatoid arthritis and osteoarthritis: A parallel investigation by semiquantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry

“…Current efforts to suppress excessive matrix degradation in RA focus mainly on metalloproteinase inhibition (43,44). Current efforts to suppress excessive matrix degradation in RA focus mainly on metalloproteinase inhibition (43,44).…”

Untitled

“…The third important feature is the diphenylether substituent, referred to as the P1' group, which is bound in the S1' pocket. The importance of the P1' group in determining the potency of virtually all MMP inhibitor series is well established [18][19][20][21] . The most striking difference between the bound conformations of the diphenylether sulfone inhibitors and that of peptidederived MMP inhibitors is the position of the P1' group relative to the α-position of the hydroxamate (Fig.…”

Structure-based Discovery of Potential Inhibitors Targeting Sodium-bile Acid Co-transporter of Carcinogenic Liver Fluke Clonorchis Sinensis

“…Analogs of this compound exhibited inhibitory effect on HCV [74]. Compound 9806452 was reported as an inhibitor of matrix metalloproteinases [75] such as gelatinase A associated with tumor metastasis [76] and stromelysin-1 found in osteoarthritis [77]. Carboxyalkyl peptides containing a biphenylylethyl group inhibits adult Schistosoma mansoni [78].…”