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

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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