MK-0767, a novel dual PPARalpha/gamma agonist, displays robust antihyperglycemic and hypolipidemic activities.
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.
Doebber
Thomas W
TW
Department of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA.
Kelly
Linda J
LJ
Zhou
Gaochao
G
Meurer
Roger
R
Biswas
Chhabi
C
Li
Ying
Y
Wu
Margaret S
MS
Ippolito
Marc C
MC
Chao
Yu-Sheng
YS
Wang
Pei-Ran
PR
Wright
Samuel D
SD
Moller
David E
DE
Berger
Joel P
JP
D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis; D019556:COS Cells; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008820:Mice, Obese; D000077205:Pioglitazone; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
D001549:Benzamides; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007328:Insulin; C487303:MK0767; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; D002784:Cholesterol; D019821:Simvastatin; D000077205:Pioglitazone