Design, synthesis, and biological evaluation of 2-(4-(methylsulfonyl)phenyl)pyridine derivatives as GPR119 agonists

Chem Biol Drug Des. 2019 Jan;93(1):67-74. doi: 10.1111/cbdd.13380. Epub 2018 Sep 12.

Abstract

This study describes the design, synthesis, and biological evaluation of a series of novel small molecule GPR119 agonists with improved potency and moderate physiochemical characteristics. Among them, the most promising compounds 19 and 20 were obtained with EC50 values of 75 and 25 nM, respectively, in vitro cAMP assays and effectively decreased blood glucose excursion in oral glucose tolerance test (OGTT) of normal mice. Furthermore, in OGTT with type 2 diabetic mice induced by streptozotocin and high-fat diet, compound 19 also showed significant reduction in blood glucose level compared to vehicle control group, which demonstrated an attractive in vitro and in vivo profile for further development.

Keywords: 2-(4-(methylsulfonyl)phenyl)pyridine; GPR119; agonistic activity; synthesis; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / pathology
  • Drug Design*
  • Glucose Tolerance Test
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / metabolism
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Mice
  • Mice, Inbred ICR
  • Protein Binding
  • Pyridines / chemistry*
  • Pyridines / metabolism
  • Pyridines / therapeutic use
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship

Substances

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