Western-style Chinese (Kampo) medicine is defined by the presenter as a methodology to exert medical effects like Chinese (Kampo) medicine by synthetic compounds (western medicine) targeting receptors or enzymes. This time I would like to propose this methodology by targeting retinoid x receptors (RXRs).So-called modern diseases, such as diabetes, cancer and AD, are closely related to lipid metabolism, which is likely to have been greatly affected by lifestyle changes in recent years. Therefore, improvement of the internal bodily environment might be an effective therapeutic approach for modern diseases. Traditional Chinese medicine (TCM) developed in China and Kampo medicine derived from TCM and progressed independently in Japan both emphasis the whole patient, focusing on the integrity of the human body and the close relationship between the human body and its environment.Retinoid X receptors (RXRs) act as homo- or heterodimers with other nuclear receptors that regulate glucose and lipid metabolism, such as PPAR, LXR and FXR. Modulating the transcriptional activities of these heterodimers by theirselves (permissive effects), RXR ligands can produce wide-ranging therapeutic effects, which other nuclear receptor ligands cannot produce. However, previously reported RXR agonists cause several adverse effects including blood TG elevation, hepatomegaly and hypothyroidism. Since these RXR agonists are full agonists, we hypothesized that these side effects are caused by the excessive activation of RXRs and moderate activation of RXR is enough for the desired medical effects.Our group developed RXR partial-agonists CBt-PMN (1 ; EC50 = 143 nM, Emax = 75%) and NEt-4IB (2 ; EC50 =169 nM , Ema = 55%) and demonstrated these compounds to exert  blood glucose-lowering and anti-inflammatory effects without body weight gain, blood TG elevation or hepatomegaly. In this presentation, our research concept and these compounds will be introduced.

Western-style Chinese (Kampo) medicine targeting retinoid X receptors (RXRs)

248th National Meeting (2014)

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