1. Fragment-Based Lead Generation of 5-Phenyl-1H-pyrazole-3-carboxamide Derivatives as Leads for Potent Factor Xia Inhibitors
- Author
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Huang Changjiang, Zheng Xuemin, Fancui Meng, Zhang Shijun, Yuan Jing, Yongnan Xu, Wei Qunchao, and Zheng Zhichao
- Subjects
0301 basic medicine ,Stereochemistry ,medicine.drug_class ,Molecular Conformation ,Pharmaceutical Science ,Carboxamide ,docking stimulation ,030204 cardiovascular system & hematology ,Pyrazole ,Molecular Dynamics Simulation ,coagulation factors ,Article ,Factor XIa ,FXIa inhibitors ,Analytical Chemistry ,lcsh:QD241-441 ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,lcsh:Organic chemistry ,Drug Discovery ,medicine ,Moiety ,Animals ,Humans ,Physical and Theoretical Chemistry ,computer-aided drug design ,thrombosis ,Anticoagulant drug ,Molecular Structure ,Hydrogen bond ,Organic Chemistry ,Anticoagulants ,In vitro ,Molecular Docking Simulation ,030104 developmental biology ,chemistry ,Chemistry (miscellaneous) ,Drug Design ,Molecular Medicine ,Pyrazoles ,Partial Thromboplastin Time ,Rabbits ,Pharmacophore ,Lead compound ,Protein Binding - 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&rsquo, 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&prime, and P2&prime, 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 &mu, M) 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.
- Published
- 2018