Fragment-Based Lead Generation of 5-Phenyl-1 H -pyrazole-3-carboxamide Derivatives as Leads for Potent Factor Xia Inhibitors.

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.