PREPARATION, RESOLUTION, AND BIOLOGICAL EVALUATION OF 5-ARYL-1,2-DIHYDRO-5H-CHROMENO[3,4-F]QUINOLINES - POTENT, ORALLY-ACTIVE, NONSTEROIDALPROGESTERONE-RECEPTOR AGONISTS

Two potent nonsteroidal progestins from the 5-aryl-1,2-dihydro-5H-chro meno[3,4-f]quinoline class (LG120746 and LG120747) were selected for s cale-up, resolution, and biological evaluation of the purified enantio mers. For each quinoline, the levorotatory enantiomer was determined t o be the more potent agonist of the human progesterone receptor isofor m B (hPR-B) (EC50 < 3 nM), but the dextrorotatory enantiomers retained significant PR modulatory activity (EC50 < 200 nM). In two in vivo ro dent models of progestational activity, a pregnancy maintenance assay and a uterine wet weight assay, the two eutomers displayed potent prog esterone-like effects. In a third model for progestational activity, t he mammary end bud assay, these compounds were significantly less acti ve. These studies demonstrate that certain members of this class of se lective progesterone receptor modulators display encouraging and poten tially useful tissue-selective progestational effects.