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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: Lyn Benson who wrote (22607)	6/23/1998 9:15:00 AM
From: Henry Niman	Respond to of 32384

Here's an earlier paper on non-steroidal progestin mimics: J Med Chem 1998 Jan 29;41(3):303-310 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. Edwards JP, West SJ, Marschke KB, Mais DE, Gottardis MM, Jones TK Department of Medicinal Chemistry, Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA. jedwards@ligand.com 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. PMID: 9464361, UI: 98125637