The discovery of (2R,4R)-N-(4-chlorophenyl)-N- (2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (PD 0348292), an orally efficacious factor Xa inhibitor.

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.

Structure-based drug design of pyrrolidine-1, 2-dicarboxamides as a novel series of orally bioavailable factor Xa inhibitors.

A novel series of pyrrolidine-1,2-dicarboxamides was discovered as factor Xa inhibitors using structure-based drug design. This series consisted of a neutral 4-chlorophenylurea P1, a biphenylsulfonamide P4 and a D-proline scaffold (1, IC(50) = 18 nM). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC(50) = 0.38 nM), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.

The endothelin A receptor antagonists PD 156707 (CI-1020) and PD 180988 (CI-1034) reverse the hypoxic pulmonary vasoconstriction in the perinatal lamb.

Endothelin-1 (ET-1) is considered an intermediary in the constrictor response of the pulmonary vasculature to hypoxia and, by extension, is assigned a prime role in the pathogenesis of pulmonary hypertension. We report here the antihypertensive action in the conscious newborn lamb of two novel endothelin A receptor antagonists, sodium 2-benzo-[1,3]dioxol-5-yl-4- (4-methoxy-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2- enoate (PD 156707) and 4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1, 1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1l6-benzo-[e][1,2]thiazine-3-carboxylic acid potassium (PD 180988), differing in chemical properties and half-life within the body. PD 156707 and PD 180988, given in the right atrium as a bolus followed by infusion, had little or no effect on pulmonary and systemic hemodynamics under normoxia. Conversely, they both reversed the pulmonary hypertension due to alveolar hypoxia while producing minor changes, or no change at all, in systemic vascular resistance. Furthermore, their pulmonary vascular effect outlasted administration. Pulmonary hypertension being elicited by infusion of the thromboxane A(2) analog, 9,11-epithio-11,12-methano-thromboxane A(2) (ONO-11113) was instead not amenable to ET(A)R inhibition. Blood levels of ET-1, which rose with hypoxia but not ONO-11113 treatment, were not changed by either antagonist. Consistent with findings in vivo, when using isolated pulmonary resistance arteries from term fetal lamb, PD 156707 curtailed the hypoxia- but not the ONO-11113-induced constriction. We conclude that PD 156707 and PD 180988 are selective inhibitors of pulmonary vasoconstriction resulting from hypoxia. Our findings support the use of these or allied compounds in the management of pulmonary hypertension in the neonate.