(E)-3-[5-di(1-methyl-1H-indol-3-yl)methyl-2-thienyl]acrylic acid (BI-1051) is a retinoid X receptor (RXR) agonist derived from a peroxisome proliferator-activated receptor ? (PPAR?) ligand 1-Di(1H-indol-3-yl)methyl-4-trifluoromethylbenzene (DIM-Ph-4-CF3). This RXR agonist represents one of the first compound with an indole as the hydrophobic ring and an additional indole moiety as the bridge substituent. However, docking pose of BI-1051 lacks important hydrophobic interactions between W305, N306 and functional group in the bridge part, which is unveiled in the crystal structure of the human RXR alpha ligand binding domain bound to the synthetic agonist compound BMS 649. Computational modeling study showed that the exchange of the position of double bond and thiophene ring improved the ligand-protein interactions with hydrophobic interfaces between methyl group in one of the indole rings and W305, N306, as well as stronger hydrogen bond between carboxylic acid and R316, A327. The multi-step syntheses and competitive RXRa binding assay of (E)-5-(3,3-bis(1-methyl-1H-indol-3-yl)prop-1-en-1-yl)thiophene-2-carboxylic acid (UI-MY45) were studied to evaluate binding affinity and selectivity towards RXR. Detailed characterization and biological data will be presented.

Synthesis and biological evaluation of a retinoid X receptor agonists identified and derived from lead optimization of a peroxisome proliferator-activated receptor ?- ligand

248th National Meeting (2014)

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