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

• Published in: Journal of medicinal chemistry 1998-01, Vol.41 (3), p.303-310
• Main Authors: Edwards, James P, West, Sarah J, Marschke, Keith B, Mais, Dale E, Gottardis, Marco M, Jones, Todd K
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Line; Female; Hormones. Endocrine system; Humans; In Vitro Techniques; Magnetic Resonance Spectroscopy; Medical sciences; Pharmacology. Drug treatments; Quinolines - chemistry; Quinolines - metabolism; Quinolines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Progesterone - agonists; Receptors, Progesterone - metabolism; Structure-Activity Relationship; Uterus - drug effects; Uterus - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9705770

Several 5-(4-chlorophenyl)-1,2-dihydro-5H-chromeno[3,4-f]quinolines were prepared to determine the effects of substitution at C(8) and C(9) on the progestational activity of this pharmacophore. In combination with a halogen (F or Cl) at C(9), replacement of the C(5) aryl group with variously substituted aryl groups resulted in optimization of the progestational activity, affording compounds with in vitro activity greater than that of progesterone as measured by a cotransfection assay using human progesterone receptor subtype-B (hPR-B). Binding affinities (K i) to hPR-A were subnanomolar in many cases. These in vitro effects were verified in vivo using a rodent model. Compound 10 (LG120794, 9-chloro-5-(4-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline) was more potent than medroxyprogesterone acetate at counterpoising the effects of estradiol benzoate in the uterine wet weight assay using immature rats.