MEDI 150 |
| Bruce E. Maryanoff, Drug Discovery, Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776 |
| In 1991, we initiated a project to find potent inhibitors of thrombin, a serine protease central to thrombosis and hemostasis, via a structure-based design approach. Study of cyclotheonamide A and its analogues led to the idea of occupying the S1’ subsite of thrombin, and ultimately to a novel series of benzothiazole ketone inhibitors. In exploring analogues of RWJ-50353 (Ki=0.2 nM), we found trypsin inhibitor RWJ-51084 (Ki=30 nM), which led to tryptase inhibitor RWJ-58643 (Ki=5 nM), also a benzothiazole ketone. Since tryptase, a main component of mast cell granules, may be important in allergic diseases such as asthma, RWJ-58643 was advanced into human clinical study. Cathepsin G is a serine protease in neutrophils that could also be important in asthma. High-throughput screening afforded nonpeptide RWJ-48345 as a modest inhibitor of Cat G (IC50=4 µM). We obtained a crystal structure of Cat G•RWJ-48345 that revealed key information for optimizing potency, especially by occupying the S3 pocket of Cat G. We devised a prototype Cat G inhibitor (Ki=50 nM) that is active in a rat peritonitis model of inflammation. |
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ACS Award in Industrial Chemistry Symposium
8:45 AM-12:00 PM, Monday, March 24, 2003 Convention Center -- La Nourvelle Ballroom C, Oral
Division of Medicinal Chemistry |