Design, synthesis and SAR of a series of 1,3,5-trisubstituted benzenes as thrombin inhibitors

A novel 1,3,5-trisubstituted benzamide thrombin inhibitor template was designed via hybridization of a known aminopyridinoneacetamide and a known 1,3,5-trisubstituted phenyl ether. Optimization of this lead afforded a novel potent series of biaryl 1,3,5-trisubstituted benzenes with excellent functional anticoagulant potency.

Graphical abstractStructure based design techniques were used to exploit the putative similarity in binding mode of an aminopyridinone thrombin inhibitor 2 and a trisubstituted benzene inhibitor 3 to generate a new lead inhibitor 4. Further optimization led to the identification of a novel series of potent thrombin inhibitor 22 with improved physical, chemical stability and in vitro functional potency.Figure optionsDownload full-size imageDownload as PowerPoint slide