681128-22-3Relevant articles and documents
Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability
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.
, p. 6900 - 6916 (2007/10/03)
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. The large (300-fold) difference in potency between analogs containing (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compounds and by molecular modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compound from this work, 41, exhibits high potency in a coagulation assay in human plasma (2×APTT = 190 nM), excellent selectivity versus the digestive enzyme trypsin (Ki = 3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F = 100%, CL = 12 mL/min/kg).
