Dataset Information

New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493.

ABSTRACT: We serendipitously found a mitochondrial uncoupler (mUncoupler), compound 1, in the process of screening for inhibitors of a gene product related to calorie restriction (CR) and longevity. Compound 1 has a unique 4-cyano-1,2,3-triazole structure which is different from any known mUncoupler and ameliorated HbA1c in Zucker diabetic fatty (ZDF) rats. However, its administration at high doses was not tolerated in an acute toxicity test in rats. We therefore tried to optimize cyanotriazole compound 1 and convert it into an agent that could be safely administered to patients with diabetes mellitus (DM) or metabolic disorders. Considering pharmacokinetic (PK) profiles, especially organ distribution targeting the liver and avoiding the brain, as well as acute toxicities and pharmacological effects of the derivatives, various conversions and substitutions at the 5-position on the cyanotriazole ring were carried out. These optimizing processes improved PK profiles and effectiveness, and acute toxicities became negligible even at high doses. We finally succeeded in developing an optimized compound, OPC-163493, as a liver-localized/targeted mUncoupler.

SUBMITTER: Okamoto T

PROVIDER: S-EPMC8264940 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493.

Okamoto Takashi T Shimada Takahiro T Matsumura Chiharu C Minoshima Hitomi H Ban Takashi T Itotani Motohiro M Shinohara Toshio T Fujita Shigekazu S Matsuda Satoshi S Sato Seiji S Kanemoto Naohide N

ACS omega 20210621 26

We serendipitously found a mitochondrial uncoupler (mUncoupler), compound <b>1</b>, in the process of screening for inhibitors of a gene product related to calorie restriction (CR) and longevity. Compound <b>1</b> has a unique 4-cyano-1,2,3-triazole structure which is different from any known mUncoupler and ameliorated HbA1c in Zucker diabetic fatty (ZDF) rats. However, its administration at high doses was not tolerated in an acute toxicity test in rats. We therefore tried to optimize cyanotriaz ...[more]

PMID: 34250356

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Dataset Information

New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493.

Publications

New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493.

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