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Bioorg Med Chem Lett. 2014 May 15;24(10):2383-7. doi: 10.1016/j.bmcl.2014.03.023. Epub 2014 Mar 27.

Discovery of structurally novel, potent and orally efficacious GPR119 agonists.

Author information

1
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States. Electronic address: palper@gnf.org.
2
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States.
3
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, United States. Electronic address: repple@gnf.org.

Abstract

Screening hit 5 was identified in a biochemical screen for GPR119 agonists. Compound 5 was structurally novel, displayed modest biochemical activity and no oral exposure, but was structurally distinct from typical GPR119 agonist scaffolds. Systematic optimization led to compound 36 with significantly improved in vitro activity and oral exposure, to elevate GLP1 acutely in an in vivo mouse model at a dose of 10mg/kg.

KEYWORDS:

GPCR agonists; GPR119; Pyrazolopyrimidines; Type 2 diabetes

PMID:
24751443
DOI:
10.1016/j.bmcl.2014.03.023
[Indexed for MEDLINE]
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