Tuning Nuclear Receptor Selectivity of Wy14,643 towards Selective Retinoid X Receptor Modulation

J Med Chem. 2019 Feb 28;62(4):2112-2126. doi: 10.1021/acs.jmedchem.8b01848. Epub 2019 Feb 15.


The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferator-activated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compound as an RXR agonist explaining the pleiotropic effects and report its systematic structure-activity relationship analysis with the discovery of specific molecular determinants driving activity on PPARs and RXRs. We have designed close analogues of the drug comprising selective and dual agonism on RXRs and PPARs that may serve as superior pharmacological tools to study the role and interplay of the nuclear receptors in various pathologies. A systematically optimized high potency RXR agonist revealed activity in vivo and active concentrations in brain. With its lack of RXR/liver X receptor-mediated side effects and superior profile compared to classical rexinoids, it establishes a new class of innovative RXR modulators to overcome key challenges in RXR targeting drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Peroxisome Proliferator-Activated Receptors / metabolism
  • Pyrimidines / chemical synthesis
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Rats
  • Retinoid X Receptors / agonists*
  • Retinoid X Receptors / metabolism
  • Structure-Activity Relationship


  • Peroxisome Proliferator-Activated Receptors
  • Pyrimidines
  • Retinoid X Receptors
  • pirinixic acid