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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:
; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1353260
Resource Type:
Journal Article
Journal Name:
Bioorganic & Medicinal Chemistry Letters
Additional Journal Information:
Journal Volume: 23; Journal Issue: 8; Journal ID: ISSN 0960-894X
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

Priestley, E. Scott, De Lucca, Indawati, Zhou, Jinglan, Zhou, Jiacheng, Saiah, Eddine, Stanton, Robert, Robinson, Leslie, Luettgen, Joseph M., Wei, Anzhi, Wen, Xiao, Knabb, Robert M., Wong, Pancras C., and Wexler, Ruth R. Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor. United States: N. p., 2013. Web. doi:10.1016/j.bmcl.2013.02.013.
Priestley, E. Scott, De Lucca, Indawati, Zhou, Jinglan, Zhou, Jiacheng, Saiah, Eddine, Stanton, Robert, Robinson, Leslie, Luettgen, Joseph M., Wei, Anzhi, Wen, Xiao, Knabb, Robert M., Wong, Pancras C., & Wexler, Ruth R. Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor. United States. doi:10.1016/j.bmcl.2013.02.013.
Priestley, E. Scott, De Lucca, Indawati, Zhou, Jinglan, Zhou, Jiacheng, Saiah, Eddine, Stanton, Robert, Robinson, Leslie, Luettgen, Joseph M., Wei, Anzhi, Wen, Xiao, Knabb, Robert M., Wong, Pancras C., and Wexler, Ruth R. Thu . "Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor". United States. doi:10.1016/j.bmcl.2013.02.013.
@article{osti_1353260,
title = {Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor},
author = {Priestley, E. Scott and De Lucca, Indawati and Zhou, Jinglan and Zhou, Jiacheng and Saiah, Eddine and Stanton, Robert and Robinson, Leslie and Luettgen, Joseph M. and Wei, Anzhi and Wen, Xiao and Knabb, Robert M. and Wong, Pancras C. and Wexler, Ruth R.},
abstractNote = {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.},
doi = {10.1016/j.bmcl.2013.02.013},
journal = {Bioorganic & Medicinal Chemistry Letters},
issn = {0960-894X},
number = 8,
volume = 23,
place = {United States},
year = {2013},
month = {2}
}