MK-0767, a novel dual PPARalpha/gamma agonist, displays robust antihyperglycemic and hypolipidemic activities

Thomas W Doebber; Linda J Kelly; Gaochao Zhou; Roger Meurer; Chhabi Biswas; Ying Li; Margaret S Wu; Marc C Ippolito; Yu-Sheng Chao; Pei-Ran Wang; Samuel D Wright; David E Moller; Joel P Berger

doi:10.1016/j.bbrc.2004.04.032

MK-0767, a novel dual PPARalpha/gamma agonist, displays robust antihyperglycemic and hypolipidemic activities

Biochem Biophys Res Commun. 2004 May 28;318(2):323-8. doi: 10.1016/j.bbrc.2004.04.032.

Authors

Thomas W Doebber¹, Linda J Kelly, Gaochao Zhou, Roger Meurer, Chhabi Biswas, Ying Li, Margaret S Wu, Marc C Ippolito, Yu-Sheng Chao, Pei-Ran Wang, Samuel D Wright, David E Moller, Joel P Berger

Affiliation

¹ Department of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA.

PMID: 15120604
DOI: 10.1016/j.bbrc.2004.04.032

Abstract

Here, we characterize the actions of MK-0767, a dual ligand of the nuclear receptors peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma. In cell-based assays, MK-0767 produced potent activation of human PPARgamma and PPARalpha with a gamma:alpha potency ratio of approximately 2. The dual agonist induced high affinity interactions of PPARalpha and PPARgamma with the transcriptional coactivator CBP in vitro. In ob/ob mice, MK-0767 normalized hyperglycemia and hyperinsulinemia with equal or greater potency and efficacy than pioglitazone. Treatment of hamsters with MK-0767 produced substantial reductions in blood cholesterol and triglycerides. In dogs, MK-0767 reduced serum cholesterol levels with a potency more than 10-fold greater than simvastatin. The efficacies of MK-0767 and simvastatin were additive when given together. We conclude that MK-0767 is a potent dual PPARalpha/gamma agonist with robust insulin sensitizing and hypolipidemic activities.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzamides / chemistry
Benzamides / pharmacology*
Blood Glucose / analysis
COS Cells
Chlorocebus aethiops
Cholesterol / blood
Cricetinae
Dogs
Dose-Response Relationship, Drug
Drug Synergism
Female
Humans
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Hypolipidemic Agents / chemistry
Hypolipidemic Agents / pharmacology*
Insulin / blood
Male
Mesocricetus
Mice
Mice, Obese
Pioglitazone
Receptors, Cytoplasmic and Nuclear / agonists*
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism
Simvastatin / pharmacology
Thiazoles / pharmacology*
Thiazolidinediones / pharmacology
Trans-Activators / metabolism
Transcription Factors / agonists*
Transcription Factors / genetics
Transcription Factors / metabolism
Transcriptional Activation / drug effects
Triglycerides / blood

Substances

Benzamides
Blood Glucose
Hypoglycemic Agents
Hypolipidemic Agents
Insulin
MK0767
Receptors, Cytoplasmic and Nuclear
Thiazoles
Thiazolidinediones
Trans-Activators
Transcription Factors
Triglycerides
Cholesterol
Simvastatin
Pioglitazone