Discovery of nonbenzamidine factor VIla inhibitors using a biaryl acid scaffold

作者：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

来源：Bioorganic & Medicinal Chemistry Letters, 2013, 23(18): 5239-5243.

DOI：10.1016/j.bmcl.2013.06.028

• Factor VIla
• 2-Aminoisoquinoline
• Inhibition

In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIla 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 VIla 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 Vlla.

• 出版日期2013-9-15