Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties

Bioorg Med Chem Lett. 2006 Nov 1;16(21):5584-9. doi: 10.1016/j.bmcl.2006.08.027. Epub 2006 Sep 11.

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.

MeSH terms

  • Administration, Oral
  • Benzamides / administration & dosage
  • Benzamides / chemical synthesis
  • Benzamides / chemistry*
  • Benzamides / pharmacology*
  • Factor Xa Inhibitors*
  • Fibrinolytic Agents / administration & dosage
  • Fibrinolytic Agents / chemical synthesis
  • Fibrinolytic Agents / chemistry*
  • Fibrinolytic Agents / pharmacology*
  • Humans
  • Treatment Outcome

Substances

  • Benzamides
  • Factor Xa Inhibitors
  • Fibrinolytic Agents