Discovery of pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists

We designed and synthesized a novel series of phenylamino- and phenoxy-substituted pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists. SAR studies indicated that electron-withdrawing substituents on the phenyl ring are important for potency and full efficacy. Compound 26 combined good potency...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2014-02, Vol.24 (3), p.949-953
Main Authors: Gillespie, Paul, Goodnow, Robert A., Saha, Goutam, Bose, Gopal, Moulik, Kakali, Zwingelstein, Catherine, Myers, Michael, Conde-Knape, Karin, Pietranico-Cole, Sherrie, So, Sung-Sau
Format: Article
Language:English
Subjects:
Agonist
Animals
Drug Discovery
GPCR
GPR119
Humans
Mice
Oral glucose tolerance test
Pyrazoles - chemical synthesis
Pyrazoles - chemistry
Pyrazoles - pharmacology
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Receptors, G-Protein-Coupled - agonists
Structure-Activity Relationship
Type 2 diabetes
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Summary:We designed and synthesized a novel series of phenylamino- and phenoxy-substituted pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists. SAR studies indicated that electron-withdrawing substituents on the phenyl ring are important for potency and full efficacy. Compound 26 combined good potency with a promising pharmacokinetic profile in mice, and lowered the glucose excursion in mice in an oral glucose-tolerance test.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.12.063