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.
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Edwards JP, West SJ, Marschke KB, Mais DE, Gottardis MM, Jones TK
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.
J Med Chem. 1998 Jan 29;41(3):303-10.
- PubMed ID
- 9464361 [ View in PubMed]
- Abstract
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 (Ki) 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Medroxyprogesterone acetate Progesterone receptor Ki (nM) 0.34 N/A N/A Details Medroxyprogesterone acetate Progesterone receptor EC 50 (nM) 0.15 N/A N/A Details Norethisterone Progesterone receptor Ki (nM) 1.9 N/A N/A Details Norethisterone Progesterone receptor EC 50 (nM) 2.2 N/A N/A Details Progesterone Progesterone receptor Ki (nM) 3.5 N/A N/A Details Progesterone Progesterone receptor EC 50 (nM) 2.9 N/A N/A Details