5-ARYL-1,2-DIHYDRO-5H-CHROMENO[3,4-F]QUINOLINES AS POTENT, ORALLY-ACTIVE, NONSTEROIDAL PROGESTERONE-RECEPTOR AGONISTS - THE EFFECT OF D-RING SUBSTITUENTS

Several rophenyl)-1,2-dihydro-5H-chromeno[3,4-f]quinolines were prepar ed to determine the effects of substitution at C(8) and C(9) on the pr ogestational activity of this pharmacophore. In combination with a hal ogen (F or Cl) at C(9), replacement of the C(5) aryl group with variou sly substituted aryl groups resulted in optimization of the progestati onal activity, affording compounds with in vitro activity greater than that of progesterone as measured by a cotransfection assay using huma n progesterone receptor subtype-B (hPR-B). Binding affinities (K-i) to hPR-A were subnanomolar in many cases. These in vitro effects were ve rified in vivo using a rodent model. Compound 10 (LG120794, hydro-2,2, 4-trimethyl-5H-chromeno[3,4-f]quinoline] was more potent than medroxyp rogesterone acetate at counterpoising the effects of estradiol benzoat e in the uterine wet weight assay using immature rats.