2. Academic Validation
  3. Discovery of structurally novel, potent and orally efficacious GPR119 agonists

Discovery of structurally novel, potent and orally efficacious GPR119 agonists

  • Bioorg Med Chem Lett. 2014 May 15;24(10):2383-7. doi: 10.1016/j.bmcl.2014.03.023.
Phil Alper 1,  Mihai Azimioara 2,  Christopher Cow 2,  Daniel Mutnick 2,  Victor Nikulin 2,  Pierre-Yves Michellys 2,  Zhiliang Wang 2,  Esther Reding 2,  Michael Paliotti 2,  Jing Li 2,  Dingjiu Bao 2,  Jocelyn Zoll 2,  Young Kim 2,  Matthew Zimmerman 2,  Todd Groessel 2,  Tove Tuntland 2,  Sean B Joseph 2,  Peter McNamara 2,  H Martin Seidel 2,  Robert Epple 3
Affiliations

Affiliations

  • 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.
PMID: 24751443 DOI: 10.1016/j.bmcl.2014.03.023
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.

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