School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
Molecules. 2018 Aug 10;23(8):2002. doi: 10.3390/molecules23082002.
FXIa is suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. In this paper, we defined 5-phenyl-1-pyrazole-3-carboxylic acid derivatives as privileged fragments for FXIa inhibitors' lead discovery. After replacing the ()-3-(5-chloro-2-(1-tetrazol-1-yl)phenyl)acrylamide moiety in compound with 5-(3-chlorophenyl)-1-pyrazole-3-carboxamide, we traveled from FXIa inhibitor to a scaffold that fused the privileged fragments into a pharmacophore for FXIa inhibitors. Subsequently, we synthesized and assessed the FXIa inhibitory potency of a series of 5-phenyl-1-pyrazole-3-carboxamide derivatives with different P1, P1' and P2'moiety. Finally, the SAR of them was systematically investigated to afford the lead compound (FXIa Ki = 90.37 nM, 1.5× aPTT in rabbit plasma = 43.33 μM) which exhibited good in vitro inhibitory potency against FXIa and excellent in vitro coagulation activities. Furthermore, the binding mode of with FXIa was studied and the results suggest that the 2-methylcyclopropanecarboxamide group of makes 2 direct hydrogen bonds with Tyr58B and Thr35 in the FXIa backbone, making binds to FXIa in a highly efficient manner.
FXIa 被认为是抗凝药物发现的主要靶点，因为它出血风险较低。在本文中，我们将 5-苯基-1-吡唑-3-羧酸衍生物定义为 FXIa 抑制剂先导化合物发现的优势片段。在将化合物 中的 ()-3-(5-氯-2-(1-四唑-1-基)苯基)丙烯酰胺部分替换为 5-(3-氯苯基)-1-吡唑-3-甲酰胺后，我们从 FXIa 抑制剂 出发，构建了一个融合优势片段的药效团，用于 FXIa 抑制剂。随后，我们合成并评估了一系列具有不同 P1、P1'和 P2'部分的 5-苯基-1-吡唑-3-甲酰胺衍生物的 FXIa 抑制活性。最后，系统地研究了它们的 SAR，得到了先导化合物 （FXIa Ki = 90.37 nM，在兔血浆中 1.5×aPTT = 43.33 μM），其对 FXIa 具有良好的体外抑制活性和优异的体外凝血活性。此外，还研究了 与 FXIa 的结合模式，结果表明 的 2-甲基环丙烷甲酰胺基团与 FXIa 骨架中的 Tyr58B 和 Thr35 形成 2 个直接氢键，使 以高效的方式与 FXIa 结合。
