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Structure-Activity Relationship Studies of 3- or 4-Pyridine Derivatives of DS-6930.

ABSTRACT: Derivatization efforts were continued to discover backups for a potent selective PPAR? modulator, DS-6930. In this Letter, the replacement of 2-pyridine ring in DS-6930 with 3- or 4-pyridyl group is reported. As the introduction of substituents on the pyridine ring did not provide potent partial agonists, modifications of benzimidazole ring were explored to discover potent intermediate agonists. 4'-Alkoxy substituted benzimidazoles failed to show potent efficacy in vivo, whereas 7'-fluoro benzimidazole 3g (DS19161384) was found to result in robust plasma glucose reductions with excellent DMPK profiles.

SUBMITTER: Shinozuka T

PROVIDER: S-EPMC6421586 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Structure-Activity Relationship Studies of 3- or 4-Pyridine Derivatives of DS-6930.

Shinozuka Tsuyoshi T Tsukada Tomoharu T Fujii Kunihiko K Tokumaru Eri E Matsui Yumi Y Wakimoto Satoko S Ogata Tsuneaki T Araki Kazushi K Sawamura Ryoko R Watanabe Nobuaki N Mori Makoto M Tanaka Jun J

ACS medicinal chemistry letters 20190226 3

Derivatization efforts were continued to discover backups for a potent selective PPARγ modulator, DS-6930. In this Letter, the replacement of 2-pyridine ring in DS-6930 with 3- or 4-pyridyl group is reported. As the introduction of substituents on the pyridine ring did not provide potent partial agonists, modifications of benzimidazole ring were explored to discover potent intermediate agonists. 4'-Alkoxy substituted benzimidazoles failed to show potent efficacy in vivo, whereas 7'-fluoro benzim ...[more]

PMID: 30891140

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