Alkoxide-catalyzed ring-opening of a novel homosaccharin derivative: synthesis of potent, selective P3-lactam thrombin inhibitors containing P4-o-alkoxycarbonylbenzylsulfonamide residues |
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Authors: | Timothy D. Owens J. Edward Semple |
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Affiliation: | Department of Medicinal Chemistry, Corvas International, Inc. 3030 Science Park Road, San Diego, CA 92121, U.S.A. |
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Abstract: | A series of lactam derivatives 1b-g featuring P4-o-alkoxycarbonylbenzylsulfonamide residues along with the potential P4-homosaccharin prodrug candidate 1h was prepared in order to probe the thrombin S3 specificity pocket. The synthesis and alkoxide-catalyzed ring opening of the novel homosaccharin intermediate 7 followed by subsequent elaboration delivered the targets 1b-h which were potent and selective thrombin inhibitors. The design, synthesis, and biological activity of these targets will be presented. |
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