Synthetic LXR agonists increase LDL in CETP species.
Liver X receptor (LXR) nuclear receptors regulate the expression of genes involved in whole body cholesterol trafficking, including absorption, excretion, catabolism, and cellular efflux, and possess both anti-inflammatory and antidiabetic actions. Accordingly, LXR is considered an appealing drug target for multiple indications. Synthetic LXR agonists demonstrated inhibition of atherosclerosis progression in murine genetic models; however, these and other studies indicated that their major undesired side effect is an increase of plasma and hepatic triglycerides. A significant impediment to extrapolating results with LXR agonists from mouse to humans is the absence in mice of cholesteryl ester transfer protein, a known LXR target gene, and the upregulation in mice but not humans of cholesterol 7alpha-hydroxylase. To better predict the human response to LXR agonism, two synthetic LXR agonists were examined in hamsters and cynomolgus monkeys. In contrast to previously published results in mice, neither LXR agonist increased HDL-cholesterol in hamsters, and similar results were obtained in cynomolgus monkeys. Importantly, in both species, LXR agonists increased LDL-cholesterol, an unfavorable effect not apparent from earlier murine studies. These results reveal additional problems associated with current synthetic LXR agonists and emphasize the importance of profiling compounds in preclinical species with a more human-like LXR response and lipoprotein metabolism.
Groot
Pieter H E
PH
Cardiovascular Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19406-0939, USA.
Pearce
Nigel J
NJ
Yates
John W
JW
Stocker
Claire
C
Sauermelch
Charles
C
Doe
Christopher P
CP
Willette
Robert N
RN
Olzinski
Alan
A
Peters
Tambra
T
d'Epagnier
Denise
D
Morasco
Kathleen O
KO
Krawiec
John A
JA
Webb
Christine L
CL
Aravindhan
Karpagam
K
Jucker
Beat
B
Burgert
Mark
M
Ma
Chun
C
Marino
Joseph P
JP
Collins
Jon L
JL
Macphee
Colin H
CH
Thompson
Scott K
SK
Jaye
Michael
M
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D002352:Carrier Proteins / Q000096:biosynthesis*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000187:drug effects; D008078:Cholesterol, LDL / Q000187:drug effects; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000819:agonists*; D006023:Glycoproteins / Q000096:biosynthesis*; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D000071518:Liver X Receptors; D008252:Macaca fascicularis; D008297:Male; D008647:Mesocricetus; D057093:Orphan Nuclear Receptors; D010648:Phenylacetates / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*
D001559:Benzhydryl Compounds; D001565:Benzoates; D001596:Benzylamines; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004268:DNA-Binding Proteins; C473027:GW 3965; D006023:Glycoproteins; D008055:Lipids; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010648:Phenylacetates; D018160:Receptors, Cytoplasmic and Nuclear; C506834:SB 742881