Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation

J Med Chem. 2016 Feb 11;59(3):1232-8. doi: 10.1021/acs.jmedchem.5b01702. Epub 2016 Jan 28.

Abstract

The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzofurans / chemical synthesis
  • Benzofurans / chemistry
  • Benzofurans / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / agonists
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism*
  • Protein Multimerization / drug effects*
  • Retinoid X Receptors / agonists
  • Retinoid X Receptors / metabolism*
  • Structure-Activity Relationship

Substances

  • Benzofurans
  • NR4A2 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Retinoid X Receptors