Sulfonamidolactam inhibitors of coagulation factor Xa

As part of an effort to identify novel backups for previously reported pyrazole-based coagulation Factor Xa inhibitors, the pyrazole 5-carboxamide moiety was replaced by 3-(sulfonylamino)-2-piperidone. This led to the identification of a structurally diverse chemotype that was further optimized to incorporate neutral or weakly basic aryl and heteroaryl P1 groups while maintaining good potency versus Factor Xa. Substitution at the sulfonamide nitrogen provided further improvements in potency and as did introduction of alternate P4 moieties.

Graphical abstractThe synthesis and SAR of N-aryl-3-(arylsulfonylamino)-piperidone inhibitors of Factor Xa is described. Compound 55 is a representative example of this series with fXa Ki = 0.043 nM.Figure optionsDownload full-size imageDownload as PowerPoint slide