Discovery of CGS 27023A, a Non-Peptidic, Potent, and Orally Active Stromelysin Inhibitor That Blocks Cartilage Degradation in Rabbits
Lawrence MacPherson(Novartis (United States)), Erol K. Bayburt(Novartis (United States)), Michael Capparelli(Novartis (United States)), Brian J. Carroll(Novartis (United States)), R Goldstein(Novartis (United States)), Michael R. Justice(Novartis (United States)), Lijuan Zhu(Novartis (United States)), Shou‐Ih Hu(Novartis (United States)), Richard Melton(Novartis (United States)), Lynn R. Fryer(Novartis (United States)), Ron L. Goldberg(Novartis (United States)), John R. Doughty(Novartis (United States)), S. Spirito(Novartis (United States)), V. Blancuzzi(Novartis (United States)), Doug Wilson(Novartis (United States)), Elizabeth O’Byrne(Novartis (United States)), Vishwas Ganu(Novartis (United States)), David T. Parker(Novartis (United States))
Cited by 325Open Access
Abstract
Structure-activity relationships of a lead hydroxamic acid inhibitor of recombinant human stromelysin were systematically defined by taking advantage of a concise synthesis that allowed diverse functionality to be explored at each position in a template. An ex vivo rat model and an in vivo rabbit model of stromelysin-induced cartilage degradation were used to further optimize these analogs for oral activity and duration of action. The culmination of these modifications resulted in CGS 27023A, a potent, orally active stromelysin inhibitor that blocks the erosion of cartilage matrix.
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