Preclinical safety profile of a liver-localized mitochondrial uncoupler

OPC-163493

Authors

  • Yuki Inoue Department of Drug Safety Research, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan. E-mail: Inoue.Yuki@otsuka.jp https://orcid.org/0000-0002-7756-5339
  • Junichi Kino Product Strategy Team 1, Product Strategy & Intelligence Office, Regulatory Affairs Department, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan https://orcid.org/0000-0003-4998-7726
  • Nobuya Ishiharada Department of Investigative Toxicology, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan https://orcid.org/0000-0002-6316-1376
  • Makoto Sato Department of Drug Safety Research, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan https://orcid.org/0000-0002-5357-904X
  • Suguru Hatanaka Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan https://orcid.org/0000-0002-8833-7841
  • Hiroyuki Yokoi Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan https://orcid.org/0000-0001-5622-1919
  • Takahiro Shimada Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan https://orcid.org/0000-0002-9253-1372
  • Seiji Sato Medicinal Chemistry Research Laboratories, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan https://orcid.org/0000-0003-2515-8261
  • Takashi Okamoto Department of Lead Discovery Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan https://orcid.org/0000-0002-4552-9480
  • Naohide Kanemoto Department of Lead Discovery Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan https://orcid.org/0000-0002-8689-0133

DOI:

https://doi.org/10.17179/excli2021-4414

Keywords:

OPC-163493, mitochondrial uncoupler (mUncoupler), liver toxicity, blood vessels toxicity, kidney toxicity

Abstract

Mitochondrial uncouplers (mUncouplers) are known to exhibit a variety of toxic effects in animals. Here we report a safety profile of an mUncoupler, OPC-163493, recently synthesized at Otsuka Pharmaceutical Co, Ltd, and its development as a therapeutic agent for treating diabetes. To understand the acute and subchronic toxicity of OPC-163493, single and repeated oral dose studies in rats, dogs, and monkeys were performed. In the rat studies, rigor mortis and increased body temperatures were observed in the high dose group. Focal necrosis, fatty change, and granular eosinophilic cytoplasm of the hepatocytes were also observed in the high dose group. In the dog studies, gastrointestinal manifestations were observed with decreased body weight and decreased food consumption in the high dose group. Necrotizing arteritis was observed in multiple organs as well as meningitis with hemorrhage in the brain. In the monkey studies, vomiting, decreased food consumption, and decreased locomotor activity were observed in the high dose group. Degeneration of the proximal convoluted tubules and the straight tubular epithelium, regeneration of the proximal tubular epithelium, and degeneration of the collecting tubular epithelium were observed. The target organs of OPC-163493 were liver, blood vessels, and kidney in rats, dogs, and monkeys, respectively. In rats, dogs, and monkeys, safety ratios were 100:1, 13:1, and 20:1, respectively, in terms of total exposure (AUC24h). These safety ratios showed clear separation between exposure to OPC-163493 in animals at NOAEL and the exposure at the effective dose in ZDF rats. This information should contribute to the drug development of new and effective mUncoupler candidates.

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Published

2022-01-11

How to Cite

Inoue, Y., Kino, J., Ishiharada, N., Sato, M., Hatanaka, S., Yokoi, H., … Kanemoto, N. (2022). Preclinical safety profile of a liver-localized mitochondrial uncoupler: OPC-163493. EXCLI Journal, 21, 213–235. https://doi.org/10.17179/excli2021-4414

Issue

Vol. 21 (2022)

Section

Original articles

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Copyright (c) 2022 Yuki Inoue, Junichi Kino, Nobuya Ishiharada, Makoto Sato, Suguru Hatanaka, Hiroyuki Yokoi, Takahiro Shimada, Seiji Sato, Takashi Okamoto, Naohide Kanemoto

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