Discovery of 1-(3'-Aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl) imidazol-1-yl] phenyl]-1 H-pyrazole-5-carboxyamide …

…, CA Teleha, JH Sun, RS Alexander, S Bai…

Index: Quan, Mimi L.; Lam, Patrick Y. S.; Han, Qi; Pinto, Donald J. P.; He, Ming Y.; Li, Renhua; Ellis, Christopher D.; Clark, Charles G.; Teleha, Christopher A.; Sun, Jung-Hui; Alexander, Richard S.; Bai, Steve; Luettgen, Joseph M.; Knabb, Robert M.; Wong, Pancras C.; Wexler, Ruth R. Journal of Medicinal Chemistry, 2005 , vol. 48, # 6 p. 1729 - 1744

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Citation Number: 161

Abstract

Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P1 ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P4 moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts ...