2. Academic Validation
  3. Antidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler

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

  • Nat Commun. 2019 May 15;10(1):2172. doi: 10.1038/s41467-019-09911-6.
Naohide Kanemoto 1,  Takashi Okamoto 2,  Koji Tanabe 3,  Takahiro Shimada 4,  Hitomi Minoshima 5,  Yuya Hidoh 4,  Masashi Aoyama 6,  Takashi Ban 7,  Yusuke Kobayashi 2,  Hikaru Ando 2,  Yuki Inoue 8,  Motohiro Itotani 9,  Seiji Sato 10
Affiliations

Affiliations

  • 1 Department of Lead Discovery Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan. [email protected].
  • 2 Department of Lead Discovery Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan.
  • 3 Department of CNS Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan.
  • 4 Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan.
  • 5 Pharmaceutical Planning Group, Otsuka Pharmaceutical Co., Ltd., 2-16-4 Shinagawa Grand Central Tower Minatominami Minato-ku, Tokyo, 108-8242, Japan.
  • 6 Biology and Translational Research Unit, Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan.
  • 7 Department of Renal and Cardiovascular Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan.
  • 8 Department of Drug Safety Research, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan.
  • 9 Quality Assurance Section (Tokushima Wajiki Factory), Quality Assurance Department, Headquarters for Product Safety and Quality Assurance, Otsuka Pharmaceutical Co., Ltd., 306-2 Otsubo Koniu aza Naka-cho Naka-gun, Tokushima, 771-5209, Japan.
  • 10 Medicinal Chemistry Research Laboratories, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan.
PMID: 31092829 DOI: 10.1038/s41467-019-09911-6
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.

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