Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor

E Scott Priestley; Indawati De Lucca; Jinglan Zhou; Jiacheng Zhou; Eddine Saiah; Robert Stanton; Leslie Robinson; Joseph M Luettgen; Anzhi Wei; Xiao Wen; Robert M Knabb; Pancras C Wong; Ruth R Wexler

doi:10.1016/j.bmcl.2013.02.013

Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor

Bioorg Med Chem Lett. 2013 Apr 15;23(8):2432-5. doi: 10.1016/j.bmcl.2013.02.013. Epub 2013 Feb 14.

Authors

E Scott Priestley¹, Indawati De Lucca, Jinglan Zhou, Jiacheng Zhou, Eddine Saiah, Robert Stanton, Leslie Robinson, Joseph M Luettgen, Anzhi Wei, Xiao Wen, Robert M Knabb, Pancras C Wong, Ruth R Wexler

Affiliation

¹ Bristol-Myers Squibb Pharmaceutical Research Institute, Experimental Station, PO Box 80500, Wilmington, DE 19880, USA. [email protected]

PMID: 23478148
DOI: 10.1016/j.bmcl.2013.02.013

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.

MeSH terms

Animals
Benzoates / chemical synthesis
Benzoates / chemistry*
Benzoates / pharmacology*
Disease Models, Animal
Factor VIIa / antagonists & inhibitors*
Factor VIIa / chemistry*
Heterocyclic Compounds, 4 or More Rings / chemical synthesis
Heterocyclic Compounds, 4 or More Rings / chemistry*
Heterocyclic Compounds, 4 or More Rings / pharmacology*
Rabbits
Structure-Activity Relationship
Thrombosis / prevention & control*

Substances

BMS 593214
Benzoates
Heterocyclic Compounds, 4 or More Rings
Factor VIIa