Bristol-Myers Squibb Research & Development, Hopewell, NJ 08534-5400, USA.
Bioorg Med Chem Lett. 2013 Sep 15;23(18):5239-43. doi: 10.1016/j.bmcl.2013.06.028. Epub 2013 Jun 20.
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.
在这封信件中，我们描述了几种含有弱碱性或非碱性 P1 基团的联芳酸因子 VIIa 抑制剂 1 的非脒类类似物的合成。我们发现 2-氨基异喹啉是苯甲脒基团（化合物 2）的极佳替代品，相对于大多数其他相关的丝氨酸蛋白酶，其对因子 VIIa 的抑制作用保持不变。出人意料的是，间苯甲酰胺 P1（化合物 21a 和 21b）被证明是一种可行的苯甲脒替代品，尽管对因子 VIIa 的效力降低了 20-40 倍。
