RXR Partial Agonist Produced by Side Chain Repositioning of Alkoxy RXR Full Agonist Retains Antitype 2 Diabetes Activity without the Adverse Effects

We
previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: 5, EC50 = 143 nM, Emax = 75%), which
showed a potent glucose-lowering effect without causing serious adverse
effects. However, it remains important to elucidate the structural
requirements for RXR efficacy and the glucose-lowering effect because
RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported
to be activated differently depending upon the chemical structure
of RXR agonists. In this work, we show that an RXR partial agonist,
NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)­amino]­pyridine-3-carboxylic
acid: 8b, EC50 = 169 nM, Emax = 55%), can be obtained simply by repositioning the
side chains (interchanging the isobutoxy and isopropoxy groups) at
the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)­amino]­pyridine-3-carboxylic
acid: 7b, EC50 = 19 nM). NEt-4IB (8b) showed antitype 2 diabetes activity without the above side effects
upon repeated oral administration to mice at 10 mg/kg/day, similarly
to 5.