Structure-based design of potent retinoid X receptor alpha agonists

J Med Chem. 2004 Apr 8;47(8):2010-29. doi: 10.1021/jm030565g.


A series of tetrahydrobenzofuranyl and tetrahydrobenzothienyl propenoic acids that showed potent agonist activity against RXRalpha were synthesized via a structure-based design approach. Among the compounds studied, 46a,b showed not only very good potency against RXRalpha (K(i) = 6 nM) but was also found to be greater than 167-fold selective vs RARalpha (K(i) > 1000 nM). This compound profiled out as a full agonist in a cell-based transient transfection assay (EC(50) = 3 nM). The two antipodes were separated via chiral chromatography, and 46b was found to be 40-fold more potent than 46a. Interestingly, cocrystallization of 46a,b with the RXRalpha protein generated a liganded structure whereby the (S)-antipode was found in the binding pocket. Given orally in db/db mice or ZDF rats, 46a,b showed a significant glucose-lowering effect and an increase in liver mass. Triglycerides decreased significantly in db/db mice but increased in the ZDF rats. A dose-dependent decrease of nonesterified free fatty acids was seen in ZDF rats but not in db/db mice. These differences indicate a species specific effect of RXR agonists on lipid metabolism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acrylates / chemical synthesis*
  • Acrylates / chemistry
  • Acrylates / pharmacology
  • Animals
  • Benzofurans / chemical synthesis*
  • Benzofurans / chemistry
  • Benzofurans / pharmacology
  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy
  • Haplorhini
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Ligands
  • Lipids / biosynthesis
  • Male
  • Mice
  • Models, Molecular
  • Radioligand Assay
  • Rats
  • Rats, Zucker
  • Receptors, Retinoic Acid / agonists*
  • Receptors, Retinoic Acid / chemistry
  • Receptors, Retinoic Acid / genetics
  • Retinoid X Receptors
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transcription Factors / agonists*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transfection


  • 3-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)tetrahydro-1-benzofuran-2-yl)-2-propenoic acid
  • Acrylates
  • Benzofurans
  • Hypoglycemic Agents
  • Ligands
  • Lipids
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Transcription Factors