Author/Authors :
James Z. Deng، نويسنده , , Daniel R. McMasters، نويسنده , , Philippe M.A. Rabbat، نويسنده , , Peter D. Williams، نويسنده , , Craig A. Coburn، نويسنده , , Youwei Yan، نويسنده , , Lawrence C. Kuo، نويسنده , , S. Dale Lewis، نويسنده , , Bobby J. Lucas Jr.، نويسنده , , Julie A. Krueger، نويسنده , , Berta Strulovici، نويسنده , , Joseph P. Vacca، نويسنده , , Terry A. Lyle، نويسنده , , Christopher S. Burgey، نويسنده ,
Abstract :
Thrombin-inhibitor X-ray crystal structures, in combination with the installation of binding elements optimized within the pyrazinone series of thrombin inhibitors, were utilized to transform a weak triazolopyrimidine lead into a series of potent oxazolopyridines. A modification intended to attenuate plasma protein binding (i.e., conversion of the P3 pyridine to a piperidine) conferred significant factor Xa activity to this series. Ultimately, these dual thrombin/factor Xa inhibitors demonstrated excellent in vitro and in vivo anticoagulant efficacy.
