Design and biological evaluation of tetrahydropyridine derivatives as novel human GPR119 agonists

Bioorg Med Chem Lett. 2020 Feb 15;30(4):126855. doi: 10.1016/j.bmcl.2019.126855. Epub 2019 Dec 3.

Abstract

A series of novel tetrahydropyridine derivatives were prepared and evaluated using cell-based measurements. Systematic optimization of general structure G-1 led to the identification of compound 35 (EC50 = 4.9 nM) and 37 (EC50 = 8.8 nM) with high GPR119 agonism activity and moderate clog P. Through single and long-term pharmacodynamic experiments, we found that compound35 showed a hypoglycemic effect and may have an effect on improving basal metabolic rate in DIO mice. Both in vitro and in vivo tests indicated that compound 35 was a potential potent GPR119 agonist in allusion to T2DM treatment.

Keywords: 1,2,3,6-Tetrahydropyridine derivatives; GPR119 agonist; OGTT; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Drug Design*
  • Glucose Tolerance Test
  • Humans
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / metabolism
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / drug therapy
  • Obesity / pathology
  • Pyrrolidines / chemistry*
  • Pyrrolidines / metabolism
  • Pyrrolidines / therapeutic use
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Solubility
  • Structure-Activity Relationship

Substances

  • Blood Glucose
  • GPR119 protein, human
  • Hypoglycemic Agents
  • Pyrrolidines
  • Receptors, G-Protein-Coupled