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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
Lead generation and optimization of novel GPR119 agonists with a spirocyclic cyclohexane structure
Kazuhito Harada1, Jun Mizukami1, Takashi Watanabe1
1Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Abstract:
We describe here the generation of a lead compound and its optimization studies that led to the identification of a novel GPR119 agonist. Based on a spirocyclic cyclohexane structure reported in our previous work, we identified compound 8 as a lead compound, being guided by ligand-lipophilicity efficiency (LLE), which linked potency and lipophilicity. Subsequent optimization studies of 8 for improvement of solubility afforded representative 21. Compound 21 had no inhibitory activity against six CYP isoforms and showed favorable pharmacokinetic properties and hypoglycemic activity in rats.
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