5-ARYL-1,2-DIHYDROCHROMENO[3,4-F]QUINOLINES - A NOVEL CLASS OF NONSTEROIDAL HUMAN PROGESTERONE-RECEPTOR AGONISTS

The development of a novel class of nonsteroidal human progesterone re ceptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihy drocoumarino[3,4-f]quinoline core 1 is the key for progestational acti vities. The structure-activity relationship (SAR) studies of the 5-ary l substituents generated a series of potent hPR agonists, which exhibi ted similar biological activity (EC50 = 8-30 nM) to the natural hormon e progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ra nging from 28% to 96%. Most of the analogues displayed similar or grea ter binding affinity (K-i = 0.41-3.6 nM) than progesterone (K-i = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in v ivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.