Design, synthesis, and structure-activity relationship of podocarpic acid amides as liver X receptor agonists for potential treatment of atherosclerosis

Bioorg Med Chem Lett. 2005 Oct 15;15(20):4574-8. doi: 10.1016/j.bmcl.2005.06.100.

Abstract

A series of podocarpic acid amides were identified as potent agonists for Liver X receptor alpha and beta subtypes, which are members of a nuclear hormone receptor superfamily that are involved in the regulation of a variety of metabolic pathways including cholesterol metabolism. We recently reported podocarpic acid anhydride and imide dimers as potent LXR agonists. Through parallel organic synthesis, we rapidly identified a series of new podocarpate leads with stable structures exemplified by adamantyl- and phenylcyclohexylmethyl-podocarpic acid amides (14 and 18). Compound 18 exhibited LXRalpha/beta 50/20 nM (binding affinity) and 33.7/35.3-fold receptor inductions. Synthesis, SAR, and biological activities of new podocarpate analogs are discussed.

MeSH terms

  • Abietanes / chemistry*
  • Abietanes / pharmacology*
  • Abietanes / therapeutic use*
  • Amides / chemistry*
  • Animals
  • Area Under Curve
  • Atherosclerosis / drug therapy*
  • Chromatography, Liquid
  • DNA-Binding Proteins / agonists*
  • Liver X Receptors
  • Male
  • Mass Spectrometry
  • Orphan Nuclear Receptors
  • Phenanthrenes / chemistry*
  • Phenanthrenes / pharmacology*
  • Phenanthrenes / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Structure-Activity Relationship

Substances

  • Abietanes
  • Amides
  • DNA-Binding Proteins
  • Liver X Receptors
  • Nr1h3 protein, rat
  • Orphan Nuclear Receptors
  • Phenanthrenes
  • Receptors, Cytoplasmic and Nuclear
  • podocarpic acid