Author/Authors :
Richard C.A. Isaacs، نويسنده , , Mark G. Solinsky، نويسنده , , Kellie J. Cutrona، نويسنده , , Christina L. Newton، نويسنده , , Adel M. Naylor-Olsen، نويسنده , , Daniel R. McMasters، نويسنده , , Julie A. Krueger، نويسنده , , S. Dale Lewis، نويسنده , , Bobby J. Lucas Jr.، نويسنده , , Lawrence C. Kuo، نويسنده , , Youwei Yan، نويسنده , , J.J. Lynch، نويسنده , , E.A. Lyle، نويسنده ,
Abstract :
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.
