Lead generation and optimization of novel GPR119 agonists with a spirocyclic cyclohexane structure. Issue 3 (1st February 2019)

• Record Type: Journal Article
• Authors: Harada, Kazuhito; Mizukami, Jun; Watanabe, Takashi; Mori, Genki; Ubukata, Minoru; Suwa, Katsunori; Fukuda, Sumiaki; Negoro, Tamotsu; Sato, Motohide; Inaba, Takashi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 3(2019)
• Page Start: 373
• Page End: 379
• Publication Date: 2019-02-01
• Subjects: GPR119 agonist -- Spirocyclic structure; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.12.041
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.