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

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.