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

Qunchao Wei,Fancui Meng,Zhichao Zheng,Changjiang Huang,Xuemin Zheng,Shijun Zhang,Yongnan Xu,Jing Yuan

doi:10.3390/molecules23082002

Abstract

FXIa is suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. In this paper, we defined 5-phenyl-1H-pyrazole-3-carboxylic acid derivatives as privileged fragments for FXIa inhibitors’ lead discovery. After replacing the (E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamide moiety in compound 3 with 5-(3-chlorophenyl)-1H-pyrazole-3-carboxamide, we traveled from FXIa inhibitor 3 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-1H-pyrazole-3-carboxamide derivatives with different P1, P1′ and P2′moiety. Finally, the SAR of them was systematically investigated to afford the lead compound 7za (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 7za with FXIa was studied and the results suggest that the 2-methylcyclopropanecarboxamide group of 7za makes 2 direct hydrogen bonds with Tyr58B and Thr35 in the FXIa backbone, making 7za binds to FXIa in a highly efficient manner.

Highlights

Cardiovascular (CV) disease continues to be the leading cause of death worldwide [1]
Despite the progresses made in past few years, there is an urgent clinical need for developing new anticoagulants to prevent and/or treat thromboembolic diseases without the risk of bleeding or with low bleeding risk
The synthetic route to target compounds 7a–7n is shown in Scheme 1

Summary

Introduction

Cardiovascular (CV) disease continues to be the leading cause of death worldwide [1]. Anticoagulants include antithrombin activators (heparins including unfractionated heparin, low molecular weight heparins and fondaparinux), vitamin K antagonists (coumarins such as warfarin), direct inhibitors of thrombin (hirudins, argatroban and dabigatran etexilate) and oral direct FXa inhibitors (rivaroxaban, apixaban, edoxaban and betrixaban) [3]. These agents possess high efficacy and relatively low cost to benefit ratio, they stillremain be associated with the life-threatening side effect of internal bleeding [4,5]. Despite the progresses made in past few years, there is an urgent clinical need for developing new anticoagulants to prevent and/or treat thromboembolic diseases without the risk of bleeding or with low bleeding risk.

Methods

Results

Conclusion