Discovery of nonbenzamidine factor VIIa inhibitors using a biaryl acid scaffold

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 18; pp. 5239 - 5243
• Main Authors: Bolton, Scott A., Sutton, James C., Anumula, Rushith, Bisacchi, Gregory S., Jacobson, Bruce, Slusarchyk, William A., Treuner, Uwe D., Wu, Shung C., Zhao, Guohua, Pi, Zulan, Sheriff, Steven, Smirk, Rebecca A., Bisaha, Sharon, Cheney, Daniel L., Wei, Anzhi, Schumacher, William A., Hartl, Karen S., Liu, Eddie, Zahler, Robert, Seiler, Steven M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.09.2013
• Subjects: 2-Aminoisoquinoline; Benzamidines; Carboxylic Acids - chemistry; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; factor VII; Factor VIIa; Factor VIIa - antagonists & inhibitors; Factor VIIa - metabolism; Humans; Inhibition; Models, Molecular; Molecular Structure; proteinase inhibitors; Serine Proteinase Inhibitors - chemical synthesis; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; serine proteinases; Structure-Activity Relationship; structure-activity relationships; 2-Aminoisoquinoline; Inhibition; Factor VIIa
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.06.028

In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20–40 fold loss in potency against factor VIIa.