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Bioorg Med Chem Lett. 2008 Mar 15;18(6):2062-6. doi: 10.1016/j.bmcl.2008.01.098. Epub 2008 Jan 30.

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

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  • 1Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.


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.

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