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

• Published in: Journal of medicinal chemistry Vol. 68; no. 4; pp. 4763 - 4786
• Main Authors: Asvos, Xenophon, El Mubarak, Mohamed A., Karampelas, Theodoros, Rampias, Theodoros, Tamvakopoulos, Constantin, Sivolapenko, Gregory B., Papakyriakou, Athanasios, Topouzis, Stavros, Vassilatis, Demetrios K., Fokas, Demosthenes
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 27.02.2025
• Subjects: Administration, Oral; Animals; Brain-Derived Neurotrophic Factor - metabolism; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - pharmacology; Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Retinoid X Receptor alpha - metabolism; Structure-Activity Relationship; Triglycerides - metabolism
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c03046

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.