Identification of a novel selective peroxisome proliferator-activated receptor alpha agonist, 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl}phenoxy)propanoic acid (LY518674), that produces marked changes in serum lipids and apolipoprotein A-1 expression.
Low high-density lipoprotein-cholesterol (HDL-c) is an important risk factor of coronary artery disease (CAD). Optimum therapy for raising HDL-c is still not available. Identification of novel HDL-raising agents would produce a major impact on CAD. In this study, we have identified a potent (IC50 approximately 24 nM) and selective peroxisome proliferator-activated receptor alpha (PPARalpha) agonist, 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl}phenoxy)propanoic acid (LY518674). In human apolipoprotein A-1 (apoA-1) transgenic mice, LY518674 produced a dose-dependent increase in serum HDL-c, resulting in 208 +/- 15% elevation at optimum dose. A new synthesis of apoA-1 contributed to the increase in HDL-c. LY518674 increased apoA-1 mRNA levels in liver. Moreover, liver slices from animals treated with LY518674 secreted 3- to 6-fold more apoA-1 than control liver slices. In cultured hepatocytes, LY518674 produced 50% higher apoA-1 secretion, which was associated with increase in radiolabeled methionine incorporation in apoA-1. Thus, LY518674 is a potent and selective PPARalpha agonist that produced a much greater increase in serum HDL-c than the known fibrate drugs. The increase in HDL-c was associated with de novo synthesis of apoA-1.
Singh
Jai Pal
JP
Lilly Research Laboratories, DC:0520, Lilly Corporate Center, Indianapolis, IN 46285, USA. singh_jaipal@lilly.com
Kauffman
Raymond
R
Bensch
William
W
Wang
Guoming
G
McClelland
Pam
P
Bean
James
J
Montrose
Chahrzad
C
Mantlo
Nathan
N
Wagle
Asavari
A
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000097:blood*; D017931:DNA Primers; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D051379:Mice; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000819:agonists*; D011422:Propionates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D014230:Triazoles / Q000494:pharmacology*
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D017931:DNA Primers; C479889:LY 518674; D047493:PPAR alpha; D011422:Propionates; D012333:RNA, Messenger; D014230:Triazoles