New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493.
ACS Omega
; 6(26): 16980-16988, 2021 Jul 06.
Article
en En
| MEDLINE
| ID: mdl-34250356
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
ACS Omega
Año:
2021
Tipo del documento:
Article
País de afiliación:
Japón
Pais de publicación:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA