Heteroaryl butyric acids and their derivatives as inhibitors of matrix metalloproteinases

Abstract

This patent application is one of several applications from the Warner-Lambert company describing small molecule, non-peptide inhibitors of matrix metalloproteinases (MMPs). The MMPs are a class of over 20 zinc-binding enzymes comprised of collagenases, stromelysins, gelatinases and membrane type- (MT-) MMPs. Elevated levels of these enzymes, with their ability to break down the extracellular matrix and basement membrane, have been implicated in the aetiology of a wide variety of disease states including osteoarthritis, rheumatoid arthritis, cancer, wound healing, atherosclerosis, heart failure, multiple sclerosis and periodontal disease. The compounds claimed in this application are members of a growing list of non-peptide, carboxylic acid based MMP inhibitors which potentially offer increased bioavailability relative to the related hydroxamates. One of the compounds exemplified is a potent inhibitor of MMP-2, with an in vitro profile comparable to Bayer’s clinical candidate, BAY 12-9566.

• arthritis
• cancer
• collagenase-3
• gelatinase A
• inflammation
• matrix metalloproteinases
• stromelysin-1