Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability

…, CM Wiscount, DR McMasters, PEJ Sanderson…

Index: Staas, Donnette D.; Savage, Kelly L.; Sherman, Vanessa L.; Shimp, Heidi L.; Lyle, Terry A.; Tran, Lekhanh O.; Wiscount, Catherine M.; McMasters, Daniel R.; Sanderson, Philip E.J.; Williams, Peter D.; Lucas Jr., Bobby J.; Krueger, Julie A.; Dale Lewis; White, Rebecca B.; Yu, Sean; Wong, Bradley K.; Kochansky, Christopher J.; Reza Anari; Yan, Youwei; Vacca, Joseph P. Bioorganic and Medicinal Chemistry, 2006 , vol. 14, # 20 p. 6900 - 6916

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Citation Number: 28

Abstract

Previous reports from our laboratories described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the P1 position. Using these as lead compounds for further optimization, we identified sites of metabolism and designed analogs with 4-fluoroproline in P2 and cyclopropane-containing side chains in P3 as an approach to reducing metabolism and improving their oral pharmacokinetic performance. ...