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Bioorg Med Chem Lett. 2013 Sep 15;23(18):5244-8. doi: 10.1016/j.bmcl.2013.06.027. Epub 2013 Jun 21.

Nonbenzamidine acylsulfonamide tissue factor-factor VIIa inhibitors.

Author information

  • 1Bristol-Myers Squibb R&D, Pennington, NJ 08534, United States. peter.glunz@bms.com

Abstract

Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P' binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype.

Copyright © 2013 Elsevier Ltd. All rights reserved.

KEYWORDS:

Factor VIIa; Serine protease inhibitors; Structure-based design; TF-FVIIa inhibitor; Tissue factor

PMID:
23845220
[PubMed - indexed for MEDLINE]
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