Synthesis and Structure-Activity Relationships of 2-Aminoacetamide Derivatives as Peroxisome Proliferator-Activated Receptor α/γ Dual Agonists

Chem Pharm Bull (Tokyo). 2015;63(8):591-602. doi: 10.1248/cpb.c15-00221.

Abstract

We describe the design, syntheses, and structure-activity relationships of novel zwitterionic compounds as nonthiazolidinedion-based peroxisome proliferator-activated receptor (PPAR) α/γ dual agonists. In our previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a sufficient glucose-lowering effect in db/db mice. However, this compound possessed an issue, i.e., the 1,3,4-oxadiazole ring was not stable in acidic conditions. Thus, we carried out further optimization to improve the stability while maintaining the other favorable profile features including potent PPARα/γ dual agonistic activity. We addressed the issue by changing the oxadiazole ring to a bioisostere amide group. These amide derivatives were stable in acidic conditions and decreased plasma glucose and plasma triglyceride levels significantly without marked weight gain.

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Drug Design
  • Female
  • Glycine / analogs & derivatives*
  • Glycine / chemical synthesis
  • Glycine / chemistry
  • Glycine / therapeutic use
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • PPAR alpha / agonists*
  • PPAR alpha / metabolism
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism
  • Rats, Zucker
  • Structure-Activity Relationship

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • PPAR alpha
  • PPAR gamma
  • glycine amide
  • Glycine