Download MendeleyPhenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with in Vivo Antithrombotic Activity.
Hangeland, J.J., Friends, T.J., Rossi, K.A., Smallheer, J.M., Wang, C., Sun, Z., Corte, J.R., Fang, T., Wong, P.C., Rendina, A.R., Barbera, F.A., Bozarth, J.M., Luettgen, J.M., Watson, C.A., Zhang, G., Wei, A., Ramamurthy, V., Morin, P.E., Bisacchi, G.S., Subramaniam, S., Arunachalam, P., Mathur, A., Seiffert, D.A., Wexler, R.R., Quan, M.L.(2014) J Med Chem 57: 9915-9932
- PubMed: 25405503
- DOI: https://doi.org/10.1021/jm5010607
- Primary Citation of Related Structures:
4TY6, 4TY7 - PubMed Abstract:
Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.
Organizational Affiliation:
Research and Development, Bristol-Myers Squibb , P.O. Box 5400, Princeton, New Jersey 08543, United States.
