Document Report Card

ID: ALA1133480

Journal: J Med Chem

Title: Rational design, synthesis, and biological activity of benzoxazinones as novel factor Xa inhibitors.

Authors: Dudley DA, Bunker AM, Chi L, Cody WL, Holland DR, Ignasiak DP, Janiczek-Dolphin N, McClanahan TB, Mertz TE, Narasimhan LS, Rapundalo ST, Trautschold JA, Van Huis CA, Edmunds JJ.

Abstract: Inappropriate thrombus formation within blood vessels is the leading cause of mortality in the industrialized world. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. From a high-throughput in vitro mass screen of our chemical library, we identified 4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-2-phenyl-2H-1, 4-benzoxazin-3(4H)-one (1a) as an inhibitor of FXa with an IC(50) of 27 microM. Through a combination of SAR studies and molecular modeling, we synthesized 3-(4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl)-1-benzenecarboximidamide (1n) which was a potent FXa inhibitor with an IC(50) of 3 nM. This compound exhibited high selectivity for FXa over other related serine proteases and was efficacious when dosed intravenously in rabbit and dog antithrombotic models.

CiteXplore: 11063603

DOI: 10.1021/jm000074l