BRF110, an Orally Active Nurr1-RXRα-Selective Rexinoid, Enhances BDNF Expression without Elevating Triglycerides

We report the discovery of a Nurr1-RXRα heterodimer-selective
rexinoid which emerged from the structural modification of aminopyrimidine
XCT0135908. Although XCT0135908 demonstrated high selectivity for
the Nurr1-RXRα heterodimer over other RXRα dimerization
partners, its poor in vivo stability and limited brain penetration
hindered its utility. Structure–activity relationship (SAR)
studies alongside bioactivity evaluations of a diverse series of substituted
pyrimidines led to BRF110, a brain-penetrant compound retaining the
selective activation of the Nurr1-RXRα heterodimer. BRF110,
as XCT0135908, protects dopaminergic cells against the Parkinson’s
disease-related toxin MPP+ and increases BDNF transcription
in mice. Notably, BRF110, in contrast to the market-approved pan-RXR
agonist bexarotene, did not elevate triglyceride levels, indicating
that enhanced heterodimer selectivity can mitigate off-target in vivo
side effects of rexinoids. These findings highlight the potential
of heterodimer-selective scaffolds as a strategy for improving the
therapeutic profile of rexinoids, addressing significant challenges
in the clinical development of RXR-targeting molecules.