Indazole-6-phenylcyclopropylcarboxylic Acids as Selective GPR120 Agonists with in Vivo Efficacy

J Med Chem. 2017 Apr 13;60(7):3187-3197. doi: 10.1021/acs.jmedchem.7b00210. Epub 2017 Apr 4.

Abstract

GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective agonists have been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series of GPR120 agonists and conducted SAR studies to optimize GPR120 potency. Furthermore, we identified a (S,S)-cyclopropylcarboxylic acid structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux was utilized to identify compounds such as 33 with lower CNS penetration, and activity in oral glucose tolerance studies was demonstrated. Differential activity was observed in GPR120 null and wild-type mice indicating that this effect operates through a mechanism involving GPR120 agonism.

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Carboxylic Acids / chemistry*
  • Carboxylic Acids / pharmacokinetics
  • Carboxylic Acids / pharmacology*
  • Humans
  • Indazoles / chemistry*
  • Indazoles / pharmacokinetics
  • Indazoles / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Receptors, G-Protein-Coupled / agonists*

Substances

  • Blood Glucose
  • Carboxylic Acids
  • FFAR4 protein, human
  • FFAR4 protein, mouse
  • Indazoles
  • Receptors, G-Protein-Coupled