Structure-based design of novel groups for use in the P1 position of thrombin inhibitor scaffolds. Part 2: N-acetamidoimidazoles

Guided by X-ray crystallography of thrombin-inhibitor complexes and molecular modeling, alkylation of the N1 nitrogen of the imidazole P1 ligand of the pyridinoneacetamide thrombin inhibitor 1 with various acetamide moieties furnished inhibitors with significantly improved thrombin potency, trypsin selectivity, functional in vitro anticoagulant potency and in vivo antithrombotic efficacy. In the pyrazinoneacetamide series, oral bioavailability was also improved.

Graphical abstractAlkylation of the N1 nitrogen of the imidazole P1 ligand of the pyridoneacetamide thrombin inhibitor 1 (RH) with various acetamide moieties furnished inhibitors (RCH2CONHR′) with significantly improved thrombin potency, trypsin selectivity, functional in vitro anticoagulant potency, and in vivo antithrombotic efficacy.Figure optionsDownload full-size imageDownload as PowerPoint slide