Novel peroxisome proliferator-activated receptor alpha agonists lower low-density lipoprotein and triglycerides, raise high-density lipoprotein, and synergistically increase cholesterol excretion with a liver X receptor agonist.
The first generation peroxisome proliferator-activated receptor (PPAR) alpha agonist gemfibrozil reduces the risk of major cardiovascular events; therefore, more potent PPARalpha agonists for the treatment of cardiovascular diseases have been actively sought. We describe two novel, potent oxybenzylglycine PPARalpha-selective agonists, BMS-687453 [N-[[3-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methyl]-N-(methoxycarbonyl)-glycine] and BMS-711939 N-[[5-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]-2-fluorophenyl]methyl]-N-(methoxycarbonyl)-glycine], that robustly increase apolipoprotein (Apo) A1 and high-density lipoprotein cholesterol in human ApoA1 transgenic mice and lower low-density lipoprotein-cholesterol and triglycerides in fat-fed hamsters. These compounds have much lower potency against mouse PPARalpha than human PPARalpha; therefore, they were tested in PPARalpha-humanized mice that do not express murine PPARalpha but express human PPARalpha selectively in the liver. We developed hepatic gene induction as a novel biomarker for efficacy and demonstrate hepatic gene induction at very low doses of these compounds. BMS-711939 induces fecal cholesterol excretion, which is further increased upon cotreatment with a liver X receptor (LXR) agonist. It is surprising that this synergistic increase upon coadministration is also observed in mice that express PPARalpha in the liver only. BMS-711939 also prevented the LXR agonist-induced elevation of serum triglycerides. Such PPARalpha agonists could be attractive candidates to explore for the treatment of cardiovascular diseases, especially in combination with a suitable LXR agonist.
Mukherjee
Ranjan
R
Department of Atherosclerosis, Bristol-Myers Squibb Company, Research and Development, Pennington, NJ 08534, USA. ranjan.mukherjee@bms.com
Locke
Kenneth T
KT
Miao
Bowman
B
Meyers
Daniel
D
Monshizadegan
Hossain
H
Zhang
Rongan
R
Search
Debra
D
Grimm
Denise
D
Flynn
Michael
M
O'Malley
Kevin M
KM
Zhang
Litao
L
Li
Jun
J
Shi
Yan
Y
Kennedy
Lawrence J
LJ
Blanar
Michael
M
Cheng
Peter T
PT
Tino
Joseph
J
Srivastava
Rai Ajit
RA
D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000819:agonists*; D004357:Drug Synergism; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008077:Lipoproteins, LDL / Q000097:blood*; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha / Q000819:agonists*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D015533:Transcriptional Activation / Q000187:drug effects; D014280:Triglycerides / Q000097:blood*
D004268:DNA-Binding Proteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D002784:Cholesterol