Discovery of liver selective non-steroidal glucocorticoid receptor antagonist as novel antidiabetic agents

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5857-62. doi: 10.1016/j.bmcl.2012.07.078. Epub 2012 Jul 31.

Abstract

Series of benzyl-phenoxybenzyl amino-phenyl acid derivatives (8a-q) are reported as non-steroidal GR antagonist. Compound 8g showed excellent h-GR binding and potent antagonistic activity (in vitro). The lead compound 8g exhibited significant oral antidiabetic and antihyperlipidemic effects (in vivo), along with liver selectivity. These preliminary results confirm discovery of potent and liver selective passive GR antagonist for the treatment of T2DM.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzyl Compounds / administration & dosage
  • Benzyl Compounds / chemistry
  • Benzyl Compounds / pharmacology*
  • Blood Glucose / drug effects
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors
  • Gene Products, tat / antagonists & inhibitors
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Liver / chemistry*
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Obese
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glucocorticoid / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Benzyl Compounds
  • Blood Glucose
  • Gene Products, tat
  • Hypoglycemic Agents
  • Receptors, Glucocorticoid
  • Focal Adhesion Protein-Tyrosine Kinases