Novel tricyclic pyrazolopyrimidines as potent and selective GPR119 agonists

Bioorg Med Chem Lett. 2014 Dec 1;24(23):5478-83. doi: 10.1016/j.bmcl.2014.10.010. Epub 2014 Oct 13.

Abstract

Systematic SAR optimization of the GPR119 agonist lead 1, derived from an internal HTS campaign, led to compound 29. Compound 29 displays significantly improved in vitro activity and oral exposure, leading to GLP1 elevation in acutely dosed mice and reduced glucose excursion in an OGTT study in rats at doses ⩾10 mg/kg.

Keywords: GPCR agonists; GPR119; Tricyclic pyrazolopyrimidines; Type 2 diabetes.

MeSH terms

  • Animals
  • Drug Discovery
  • Mice
  • Molecular Structure
  • Pyrimidines / chemical synthesis*
  • Rats
  • Receptors, G-Protein-Coupled / drug effects*
  • Structure-Activity Relationship

Substances

  • GPR119 protein, human
  • Pyrimidines
  • Receptors, G-Protein-Coupled
  • pyrimidine