title: Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor.
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.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Experimental Station, PO Box 80500, Wilmington, DE 19880, USA. scott.priestley@bms.com
authors.forename: E Scott
authors.initials: ES
authors.lastname: Priestley
authors.forename: Indawati
authors.initials: I
authors.lastname: De Lucca
authors.forename: Jinglan
authors.initials: J
authors.lastname: Zhou
authors.forename: Jiacheng
authors.initials: J
authors.lastname: Zhou
authors.forename: Eddine
authors.initials: E
authors.lastname: Saiah
authors.forename: Robert
authors.initials: R
authors.lastname: Stanton
authors.forename: Leslie
authors.initials: L
authors.lastname: Robinson
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Anzhi
authors.initials: A
authors.lastname: Wei
authors.forename: Xiao
authors.initials: X
authors.lastname: Wen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
mesh_terms: D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004195:Disease Models, Animal; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000517:prevention & control*
chemical_list: C553827:BMS 593214; D001565:Benzoates; D006576:Heterocyclic Compounds, 4 or More Rings; D015942:Factor VIIa