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Lead generation and optimization of novel GPR119 agonists with a spirocyclic cyclohexane structure.

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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Harada K,Mizukami J,Watanabe T,Mori G,Ubukata M,Suwa K,Fukuda S,Negoro T,Sato M,Inaba T

doi

10.1016/j.bmcl.2018.12.041

subject

Has Abstract

pub_date

2019-02-01 00:00:00

pages

373-379

issue

3

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(18)30988-0

journal_volume

29

pub_type

杂志文章

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