Download MendeleyDiscovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor.
Priestley, E.S., De Lucca, I., Zhou, J., Zhou, J., Saiah, E., Stanton, R., Robinson, L., Luettgen, J.M., Wei, A., Wen, X., Knabb, R.M., Wong, P.C., Wexler, R.R.(2013) Bioorg Med Chem Lett 23: 2432-2435
- PubMed: 23478148
- DOI: https://doi.org/10.1016/j.bmcl.2013.02.013
- Primary Citation of Related Structures:
4ISH - PubMed Abstract:
A 6-amidinotetrahydroquinoline screening hit was driven to a structurally novel, potent, and selective FVIIa inhibitor through a combination of library synthesis and rational design. An efficient gram-scale synthesis of the active enantiomer BMS-593214 was developed, which required significant optimization of the key Povarov annulation. Importantly, BMS-593214 showed antithrombotic efficacy in a rabbit arterial thrombosis model. A crystal structure of BMS-593214 bound to FVIIa highlights key contacts with Asp 189, Lys 192, and the S2 pocket.
Organizational Affiliation:
Bristol-Myers Squibb Pharmaceutical Research Institute, Experimental Station, PO Box 80500, Wilmington, DE 19880, USA. scott.priestley@bms.com
