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

Research paper by Donnette D DD Staas, Kelly L KL Savage, Vanessa L VL Sherman, Heidi L HL Shimp, Terry A TA Lyle, Lekhanh O LO Tran, Catherine M CM Wiscount, Daniel R DR McMasters, Philip E J PE Sanderson, Peter D PD Williams, Bobby J BJ Lucas, Julie A JA Krueger, S Dale SD Lewis, Rebecca B RB White, Sean S Yu, et al.

Indexed on: 28 Jul '06Published on: 28 Jul '06Published in: Bioorganic & Medicinal Chemistry


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 (2xAPTT=190 nM), excellent selectivity versus the digestive enzyme trypsin (K(i)=3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F=100%, CL=12 mL/min/kg).