Title of article :
Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties
Author/Authors :
Donald J.P. Pinto، نويسنده , , Robert A. Galemmo Jr.، نويسنده , , Mimi L. Quan، نويسنده , , Michael J. Orwat، نويسنده , , Charles Clark، نويسنده , , Renhua Li، نويسنده , , Brian Wells، نويسنده , , Francis Woerner، نويسنده , , Richard S. Alexander، نويسنده , , Karen A. Rossi، نويسنده , , Angela Smallwood، نويسنده , , Pancras C. Wong، نويسنده , , Joseph M. Luettgen، نويسنده , , Alan R. Rendina، نويسنده , , Robert M. Knabb، نويسنده , , Kan He، نويسنده , , Ruth R. Wexler، نويسنده , , Patrick Y.S. Lam، نويسنده ,
Abstract :
The bicyclic dihydropyrazolopyridinone scaffold allowed for incorporation of multiple P1 moieties with subnanomolar binding affinities for blood coagulation factor Xa. The compound 3-[6-(2′-dimethylaminomethyl-biphenyl-4-yl)-7-oxo-3-trifluoro-methyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridine-l-yl]-benzamide 6d shows good fXa potency, selectivity, in vivo efficacy and oral bioavailability. Compound 6d was selected for further pre-clinical evaluations.
Keywords :
Rabbit AV Shunt efficacy , half-life , thrombin , BMS-740808 , Selectivity , Dog ‘N-in-one’ pharmacokinetics , Oral bioavailability , Clearance , factor Xa , Vdss , Trypsin , blood coagulation , Aminobenzisoxazole , P-methoxyphenyl and 3-phenylcarboxamido P1
