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

[Image: see text] 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 mU...

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Autores principales: Okamoto, Takashi, Shimada, Takahiro, Matsumura, Chiharu, Minoshima, Hitomi, Ban, Takashi, Itotani, Motohiro, Shinohara, Toshio, Fujita, Shigekazu, Matsuda, Satoshi, Sato, Seiji, Kanemoto, Naohide
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264940/
https://www.ncbi.nlm.nih.gov/pubmed/34250356
http://dx.doi.org/10.1021/acsomega.1c01993
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author Okamoto, Takashi
Shimada, Takahiro
Matsumura, Chiharu
Minoshima, Hitomi
Ban, Takashi
Itotani, Motohiro
Shinohara, Toshio
Fujita, Shigekazu
Matsuda, Satoshi
Sato, Seiji
Kanemoto, Naohide
author_facet Okamoto, Takashi
Shimada, Takahiro
Matsumura, Chiharu
Minoshima, Hitomi
Ban, Takashi
Itotani, Motohiro
Shinohara, Toshio
Fujita, Shigekazu
Matsuda, Satoshi
Sato, Seiji
Kanemoto, Naohide
author_sort Okamoto, Takashi
collection PubMed
description [Image: see text] 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.
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spelling pubmed-82649402021-07-09 New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493 Okamoto, Takashi Shimada, Takahiro Matsumura, Chiharu Minoshima, Hitomi Ban, Takashi Itotani, Motohiro Shinohara, Toshio Fujita, Shigekazu Matsuda, Satoshi Sato, Seiji Kanemoto, Naohide ACS Omega [Image: see text] 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. American Chemical Society 2021-06-21 /pmc/articles/PMC8264940/ /pubmed/34250356 http://dx.doi.org/10.1021/acsomega.1c01993 Text en © 2021 The Authors. Published by American Chemical Society Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Okamoto, Takashi
Shimada, Takahiro
Matsumura, Chiharu
Minoshima, Hitomi
Ban, Takashi
Itotani, Motohiro
Shinohara, Toshio
Fujita, Shigekazu
Matsuda, Satoshi
Sato, Seiji
Kanemoto, Naohide
New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493
title New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493
title_full New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493
title_fullStr New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493
title_full_unstemmed New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493
title_short New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493
title_sort new approach to drug discovery of a safe mitochondrial uncoupler: opc-163493
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264940/
https://www.ncbi.nlm.nih.gov/pubmed/34250356
http://dx.doi.org/10.1021/acsomega.1c01993
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