Design, synthesis and biological evaluation of a novel class of potent TGR5 agonists based on a 4-phenyl pyridine scaffold

Eur J Med Chem. 2013 Nov:69:55-68. doi: 10.1016/j.ejmech.2013.07.050. Epub 2013 Aug 13.

Abstract

TGR5, a GPCR, is involved in energy and glucose homeostasis, and as such, is a target for the treatment of diabetes, obesity and other metabolic syndromes. A new class of TGR5 agonists based on a 4-phenyl pyridine scaffold was designed, synthesized and evaluated in vitro and in vivo. Extensive structure-activity relationship studies are reported herein. The most potent compounds 15a, 18b and 18c showed comparable activity with the lead compound 2. 15a had the best potency in vitro but displayed an unfavorable pharmacokinetic profile and was found to be ineffective during an oral glucose tolerance test in imprinting control region mice at a dose of 50 mg/kg.

Keywords: 4-Phenyl pyridine; Diabetes; GPCR; TGR5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Glucose / administration & dosage
  • Glucose Tolerance Test
  • Humans
  • Male
  • Mice
  • Mice, Inbred ICR
  • Molecular Structure
  • Pyridines / administration & dosage
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology*
  • Receptors, G-Protein-Coupled / agonists*
  • Structure-Activity Relationship

Substances

  • GPBAR1 protein, human
  • Pyridines
  • Receptors, G-Protein-Coupled
  • 4-phenylpyridine
  • Glucose