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
  • 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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