Exerting strong anti-inflammatory effects, steroidal anti-inflammatory drugs produce serious side effects including hyperglycemia, ulcer disorder by inhibition of prostaglandin production, infections by excessive immuno-suppression, and Cushing's syndrome. These back grounds prompted us to create new anti-inflammatory drugs which can be replaced for steroidal anti-inflammatory drugs. Retinoid X receptors (RXRs) form heterodimers with peroxisome proliferator-activated receptor (PPAR) and liver X receptors (LXRs) which are known to exert anti-inflammatory effects through the suppression of NF-kB by their activation. These receptors form heterodimers with retinoid x receptors (RXRs), and these heterodimers can be activated by RXR agonists alone (permissive effect). Since RXR anti-inflammatory effects are thought to be produced differently by glucocorticoid receptor (GR), RXR agonists are expected as new anti-inflammatory drugs. However previously reported RXR agonists are full agonists and produce blood triglyceride elevation, hypothyroidism, weight gain and hepatomegaly. We hypothesized that these side effects are caused by the excessive activation of RXRs and moderate activation of RXRs is enough for the desired medical effects. This time, 6-[ethyl(4-isobutoxy-3-isopropylphenyl)amino]-3-pyridinecarboxylic acid (1  : NEt-4IB), which is a regioisomer of a RXR full agonist NEt-3IB (2  ), was found as a RXR partial agonist. Compound 1  inhibits nitric oxide (NO) production in LPS-stimulated RAW 264.7 cells at 10 mM by ca 50%. Moreover 1  showed anti-inflammatory effect in NBD-Cl induced inflammatory bowel disease model mice at 10 mg/kg oral administration, though prednisolone and 2   did not show the effects. And 1  did not produce hepatomegaly and hyperglicemia.

RXR partial agonist NEt-4IB exerts therapeutic effects on inflammatory bowel disease without the side effects of RXR full agonists

248th National Meeting (2014)

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