Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor
Journal Article
·
· Bioorganic & Medicinal Chemistry Letters
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.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1353260
- Journal Information:
- Bioorganic & Medicinal Chemistry Letters, Vol. 23, Issue 8; ISSN 0960-894X
- Country of Publication:
- United States
- Language:
- ENGLISH
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