Preparation, resolution, and biological evaluation of 5-aryl-1, 2-dihydro-5H-chromeno[3,4-f]quinolines: potent, orally active, nonsteroidal progesterone receptor agonists

J Med Chem. 1998 Jul 16;41(15):2779-85. doi: 10.1021/jm980190c.

Abstract

Two potent nonsteroidal progestins from the 5-aryl-1, 2-dihydro-5H-chromeno[3,4-f]quinoline class (LG120746 and LG120747) were selected for scale-up, resolution, and biological evaluation of the purified enantiomers. For each quinoline, the levorotatory enantiomer was determined to be the more potent agonist of the human progesterone receptor isoform B (hPR-B) (EC50 < 3 nM), but the dextrorotatory enantiomers retained significant PR modulatory activity (EC50 < 200 nM). In two in vivo rodent models of progestational activity, a pregnancy maintenance assay and a uterine wet weight assay, the two eutomers displayed potent progesterone-like effects. In a third model for progestational activity, the mammary end bud assay, these compounds were significantly less active. These studies demonstrate that certain members of this class of selective progesterone receptor modulators display encouraging and potentially useful tissue-selective progestational effects.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Benzopyrans* / chemical synthesis
  • Benzopyrans* / chemistry
  • Benzopyrans* / isolation & purification
  • Benzopyrans* / pharmacology
  • Chromatography, High Pressure Liquid
  • Crystallography, X-Ray
  • Embryo Implantation / drug effects
  • Female
  • Humans
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / drug effects
  • Mice
  • Mice, Inbred ICR
  • Mitosis / drug effects
  • Molecular Conformation
  • Organ Size / drug effects
  • Ovariectomy
  • Pregnancy
  • Quinolines* / chemical synthesis
  • Quinolines* / chemistry
  • Quinolines* / isolation & purification
  • Quinolines* / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Progesterone / agonists*
  • Receptors, Progesterone / metabolism
  • Stereoisomerism
  • Uterus / drug effects
  • Uterus / growth & development

Substances

  • Benzopyrans
  • LG 120746
  • LG 120747
  • Quinolines
  • Receptors, Progesterone