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. Epub 2014 Mar 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy
  • Humans
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptors, G-Protein-Coupled / agonists*
  • Structure-Activity Relationship

Substances

  • GPR119 protein, human
  • Gpr119 protein, mouse
  • Hypoglycemic Agents
  • Pyrazoles
  • Pyrimidines
  • Receptors, G-Protein-Coupled