Design and synthesis of dual peroxisome proliferator-activated receptors gamma and delta agonists as novel euglycemic agents with a reduced weight gain profile

J Med Chem. 2006 Sep 21;49(19):5649-52. doi: 10.1021/jm060617c.

Abstract

The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) gamma/delta agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR gamma/delta agonist profile (IC(50) = 19 nM/4 nM; EC(50) = 102 nM/6 nM for hPPARgamma and hPPARdelta, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Cell Line
  • Diabetes Mellitus, Type 2 / drug therapy
  • Drug Design
  • Dyslipidemias / drug therapy
  • Female
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Male
  • Mice
  • PPAR alpha / genetics
  • PPAR delta / agonists*
  • PPAR gamma / agonists*
  • Phenyl Ethers / chemical synthesis*
  • Phenyl Ethers / chemistry
  • Phenyl Ethers / pharmacology
  • Phenylpropionates / chemical synthesis*
  • Phenylpropionates / chemistry
  • Phenylpropionates / pharmacology
  • Radioligand Assay
  • Stereoisomerism
  • Transcriptional Activation
  • Weight Gain / drug effects*

Substances

  • 3-(4-(3-(4-chloro-2-phenoxyphenoxy)butoxy)-2-ethylphenyl)propionic acid
  • Blood Glucose
  • Hypoglycemic Agents
  • PPAR alpha
  • PPAR delta
  • PPAR gamma
  • Phenyl Ethers
  • Phenylpropionates