Antidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler

Naohide Kanemoto (), Takashi Okamoto, Koji Tanabe, Takahiro Shimada, Hitomi Minoshima, Yuya Hidoh, Masashi Aoyama, Takashi Ban, Yusuke Kobayashi, Hikaru Ando, Yuki Inoue, Motohiro Itotani and Seiji Sato
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Naohide Kanemoto: Otsuka Pharmaceutical Co., Ltd.
Takashi Okamoto: Otsuka Pharmaceutical Co., Ltd.
Koji Tanabe: Otsuka Pharmaceutical Co., Ltd.
Takahiro Shimada: Otsuka Pharmaceutical Co., Ltd.
Hitomi Minoshima: Otsuka Pharmaceutical Co., Ltd.
Yuya Hidoh: Otsuka Pharmaceutical Co., Ltd.
Masashi Aoyama: Otsuka Pharmaceutical Co., Ltd.
Takashi Ban: Otsuka Pharmaceutical Co., Ltd.
Yusuke Kobayashi: Otsuka Pharmaceutical Co., Ltd.
Hikaru Ando: Otsuka Pharmaceutical Co., Ltd.
Yuki Inoue: Otsuka Pharmaceutical Co., Ltd.
Motohiro Itotani: Otsuka Pharmaceutical Co., Ltd.
Seiji Sato: Otsuka Pharmaceutical Co., Ltd.

Nature Communications, 2019, vol. 10, issue 1, 1-20

Abstract: Abstract Inducing mitochondrial uncoupling (mUncoupling) is an attractive therapeutic strategy for treating metabolic diseases because it leads to calorie-wasting by reducing the efficiency of oxidative phosphorylation (OXPHOS) in mitochondria. Here we report a safe mUncoupler, OPC-163493, which has unique pharmacokinetic characteristics. OPC-163493 shows a good bioavailability upon oral administration and primarily distributed to specific organs: the liver and kidneys, avoiding systemic toxicities. It exhibits insulin-independent antidiabetic effects in multiple animal models of type I and type II diabetes and antisteatotic effects in fatty liver models. These beneficial effects can be explained by the improvement of glucose metabolism and enhancement of energy expenditure by OPC-163493 in the liver. Moreover, OPC-163493 treatment lowered blood pressure, extended survival, and improved renal function in the rat model of stroke/hypertension, possibly by enhancing NO bioavailability in blood vessels and reducing mitochondrial ROS production. OPC-163493 is a liver-localized/targeted mUncoupler that ameliorates various complications of diabetes.

Date: 2019
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DOI: 10.1038/s41467-019-09911-6

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