Discovery and development of dimeric podocarpic acid leads as potent agonists of liver X receptor with HDL cholesterol raising activity in mice and hamsters

Bioorg Med Chem Lett. 2005 Jun 2;15(11):2824-8. doi: 10.1016/j.bmcl.2005.03.100.

Abstract

Liver X receptors are nuclear receptors that regulate metabolism of cholesterol. They are activated by oxysterols resulting in increased transcription of the ABCA1 gene, promoting cholesterol efflux and HDL formation. We have identified podocarpic acid anhydride as a 1nM agonist of LXRalpha and beta receptors. Functionally this agonist was over 8-10-fold better activator of LXR receptors compared to one of the natural ligands, 22-(R)-hydroxy cholesterol, in HEK-293 cells. An imide analog increased the level of HDL by 26%, decreased LDL by 10.6%, and increased triglyceride by 51% in hamsters. Discovery, synthesis, SAR and details of the activities of dimers have been described.

MeSH terms

  • Abietanes / chemistry
  • Abietanes / pharmacokinetics
  • Abietanes / pharmacology*
  • Animals
  • Area Under Curve
  • Biotransformation
  • Cell Line
  • Cholesterol, HDL / blood*
  • Cricetinae
  • Dimerization
  • Humans
  • Male
  • Mice
  • Phenanthrenes / chemistry
  • Phenanthrenes / pharmacokinetics
  • Phenanthrenes / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Structure-Activity Relationship

Substances

  • Abietanes
  • Cholesterol, HDL
  • Phenanthrenes
  • Receptors, Cytoplasmic and Nuclear
  • podocarpic acid