BRF110, anOrally Active Nurr1-RXRα-SelectiveRexinoid, 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.