51. Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties
- Author
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Joseph M. Luettgen, Robert M. Knabb, Brian Wells, Patrick Y.S. Lam, Richard S. Alexander, Kan He, Angela Smallwood, Mimi L. Quan, Robert A. Galemmo, Charles G. Clark, Ruth R. Wexler, Donald J. P. Pinto, Pancras C. Wong, Michael J. Orwat, Francis J. Woerner, Karen A. Rossi, Alan R. Rendina, and Renhua Li
- Subjects
Tertiary amine ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Administration, Oral ,Pharmacology ,Biochemistry ,Thrombin ,Fibrinolytic Agents ,In vivo ,Drug Discovery ,Pyrazolopyridine ,medicine ,Potency ,Humans ,Molecular Biology ,Bicyclic molecule ,biology ,Chemistry ,Organic Chemistry ,Bioavailability ,Treatment Outcome ,Enzyme inhibitor ,Benzamides ,biology.protein ,Molecular Medicine ,medicine.drug ,Factor Xa Inhibitors - 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.
- Published
- 2006