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SYNTEX METALLOPROTEINASE INHIBITORS RESEARCH DEPENDS ON DEVELOPMENT OF ORAL, BIOAVAILABLE COMPOUNDS FOR THE TREATMENT OF RHEUMATOID AND OSTEOARTHRITIS

Executive Summary

Syntex" matrix metalloproteinase (MMP) inhibitor program hinges on the development of oral, bio-available compounds for potential use in treating rheumatoid arthritis and osteoarthritis, Syntex Research VP and Director Harold Van Wart indicated at a Sept. 27-29 conference entitled "Beyond NSAIDS: New Therapeutics for Inflammation." "The major problem in the field right now is that most of the inhibitors, that we and our competitors have, have very poor pharmacokinetic properties," Van Wart said. "Their oral bioavailability is not very good, and the task as I see it now... is to make [them] more orally bioavailable." SmithKline Beecham and Roche are conducting preclinical work on metalloproteinase inhibitors. Van Wart predicted, that "once oral, active, bioavailable inhibitors are [in our hands] there's a substantial chance that they'll be able to block [cartilage degradation] in both RA [rheumatoid arthritis] and OA [osteoarthritis]." Under an R&D agreement, Syntex may provide up to $12 mil. over the next three to four years to San Diego-based Agouron Pharmaceuticals for design and development of NMPs ("The Pink Sheet" June 14, T&G-4). Agouron is "refining" MMP inhibitors through X-ray crystallography. During the conference, held in New Orleans and sponsored by Cambridge Healthtech Institute, companies presented their research into treating inflammatory diseases based on a variety of approaches, including enzyme inhibitors, receptor antagonists and mediator release inhibitors. Session chair, Pfizer Inflammation Research Manager Niall Doherty pointed out the challenges for the next class of anti- inflammatory products beyond nonsteroidal anti-inflammatory drugs. "To go beyond NSAIDS, we have to minimize" the serious gastrointestinal and renal side effects, provide greater analgesic and anti-edema efficacy and inhibit tissue damage that results in decreased loss of function, Doherty said. Syntex' Van Wart explained that many inflammatory diseases are characterized by degradation of extracellular matrix and "this destruction is believed to be mediated by a class of enzymes, or largely mediated by a class of enzymes called matrix metalloproteinases." Van Wart said that "one post-NSAID type drug target strategy involves trying to develop specific inhibitors of the target metalloproteinases with the hope of trying to be able to block the terminal destruction of matrix that leads to irreversible damage" in many diseases. In taking this approach, Syntex has had to deal with "the fact that there are nine or more individual MMPs and these have a multitude of potential substrates," Van Wart said. "Some of them we want to turn over and some of them we don't want to turn over" because they are involved with normal processes. "It's my belief and it's many other people's belief that the most critical thing in protecting cartilage is to protect the fibril network," Van Wart said. Therefore, fibroblast collagenase and neutrophil collagenase are important targets, he noted. The Syntex exec pointed out that Roche and SmithKline have reported on the use of matrix metalloproteinase inhibitors in animal models of arthritis. "Some data presented at [an MMP] conference a couple of weeks ago shows that these compounds have unexpectedly good behavior at blocking matrix destruction from the point of view of protecting cartilage." Conference participants pointed out that another hurdle facing companies is that animal models may not be relevant to human inflammatory diseases. Another issue is whether these products will be viewed as being cost effective. "Can we get these buying consortiums to look at our drug or are we developing drugs that only a few people will take?" Glycomed VP Chemistry R&D, John Musser asked. "Certainly that aspect is going to make or break a lot of us."
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