Optimization of oxadiazole derivatives with a spirocyclic cyclohexane structure as novel GPR119 agonists.

Autor: Harada K; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. Electronic address: kazuhito.harada@jt.com., Mizukami J; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Watanabe T; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Mori G; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Ubukata M; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Suwa K; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Fukuda S; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Negoro T; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Sato M; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan., Inaba T; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Aug 15; Vol. 29 (16), pp. 2100-2106. Date of Electronic Publication: 2019 Jul 03.
DOI: 10.1016/j.bmcl.2019.07.004
Abstrakt: We describe here a novel GPR119 agonist 24, which showed a potent and long-acting hypoglycemic effect in rats via oral dosing. For the discovery of 24, we chose compound 5, which possessed an oxadiazole linker, as a lead compound among our spirocyclic cyclohexane GPR119 agonist series, taking into account its lower plasma protein binding nature. 3,5-Difluoro and 4-methylsulfonylmethy groups on the left side phenyl group, and a gem-difluoro group on the right side of 24 are important for its agonist potency and metabolic stability, respectively.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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