Synthesis of novel homeostasis modulators by "Westernized Kampo Medicine"
—Retinoid X Receptor Partial-Agonists Exert Anti-type 2 Diabetes Effects with Less Adverse Effects than Full-Agonists—
"Westernized Kampo Medicine" is a novel approach in modern medicine, defined by Dr. Hiroki Kakuta, that intends to exhibit the effects of Japanese Kampo Medicine with small molecules (Ref. 1). Japanese Kampo Medicine was developed in Japan, branching from traditional Chinese Medicine (Oriental Medicine). In contrast to Western Medicine, which has a well-regarded therapeutic method of treating diseases by using drugs focused on target molecules such as receptors or enzymes specifically related to each disease, Oriental Medicine is a systematic treatment based on consideration of a patient's homeostatic condition and environmental factors to determine a patient's well-being. In particular, Chinese herbs are one of the tools used for treatments in Oriental Medicine. Recent common diseases such as diabetes, Alzheimer's Disease, and cancer are considered to be closely related to patients' life styles, and are expected to be diagnosed and be treated by "Westernized Kampo Medicine".
Dr. Kakuta has recently demonstrated this new concept from his exploratory research on the study of Retinoid X Receptor (RXR). By this concept, a new drug, a small molecule as opposed to a Chinese herb of Oriental Medicine, was synthesized, selected and proved to work as a partial-agonist to its target molecule, which exerts significant efficacy with less adverse effects.
RXRs act as dimers that consist of peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs) or other receptors (Figure 1). PPARs and LXRs are known to control glucose/lipid metabolism and develop anti-inflammatory effects through the suppression of NF-κB. The hetero-dimers can be activated by RXR agonists alone (Permissive Effect). It is reported that RXR agonists have anti-diabetic and anti-inflammatory effects. However, the RXR agonists reported previously are full-agonists and lead to the elevation of the triglyceride (TG) level in blood, hypothyroidism, weight gain, and hepatomegaly. Dr. Kakuta and his colleagues hypothesized that these adverse effects are caused by the excessive activation of RXR as a full-agonist, and that more moderate activation of RXR as a partial-agonist is sufficient for exhibiting the desired drug efficacy.
Our synthesis method has the following features:
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6. Manuscript in preparation
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Contact: Mototaka Senda, Ph.D.,
US & EU Representative of Intellectual Property Office,
Okayama University, 2450 Peralta Blvd. #119, Fremont, CA 94536, USA