The Discovery of (2<i>R</i>,4<i>R</i>)‐<i>N</i>‐(4‐chlorophenyl)‐<i>N</i>‐ (2‐fluoro‐4‐(2‐oxopyridin‐1(2<i>H</i>)‐yl)phenyl)‐4‐methoxypyrrolidine‐1,2‐dicarboxamide (PD 0348292), an Orally Efficacious Factor Xa Inhibitor

Abstract

Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.