Discovery and SAR of Natural-Product-Inspired RXR Agonists with Heterodimer Selectivity to PPAR delta-RXR

摘要

A known natural product, magnaldehyde B, was identified as an agonist of retinoid X receptor (RXR) alpha. Magnaldehyde B was isolated from Magnolia obovata (Magnoliaceae) and synthesized along with more potent analogs for screening of their RXR alpha agonistic activities. Structural optimization of magnaldehyde B resulted in the development of a candidate molecule that displayed a 440-fold increase in potency. Receptor-ligand docking simulations indicated that this molecule has the highest affinity with the ligand binding domain of RXR alpha among the analogs synthesized in this study. Furthermore, the selective activation of the peroxisome proliferator-activated receptor (PPAR) delta-RXR heterodimer with a stronger efficacy compared to those of PPAR alpha-RXR and PPAR gamma-RXR was achieved in luciferase reporter assays using the PPAR response element driven reporter (PPRE-Luc). The PPAR delta activity of the molecule was significantly inhibited by the antagonists of both RXR and PPAR delta, whereas the activity of GWS01516 was not affected by the RXR antagonist. Furthermore, the molecule exhibited a particularly weak PPAR delta agonistic activity in reporter gene assays using the Gal4 hybrid system. The obtained data therefore suggest that the weak PPAR delta agonistic activity of the optimized molecule is synergistically enhanced by its own RXR agonistic activity, indicating the potent agonistic activity of the PPAR delta-RXR heterodimer.