Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) delta-selective agonists.
A series of 3-(4-alkoxyphenyl)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) delta-selective agonists, based on our previously discovered potent human PPARalpha/delta dual agonist TIPP-401 as a lead compound. Structure-activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPARdelta transactivation activity and highest PPARdelta selectivity. The (S)-enantiomer of a representative compound exhibited extremely potent PPARdelta transactivation activity, comparable with or somewhat superior to that of the known PPARdelta-selective agonist, GW-501516. The representative compound regulated the expression of genes involved in lipid and glucose homeostasis, and should be useful not only as a chemical tool to study PPARdelta function, but also as a candidate drug for the treatment of metabolic syndrome.
Kasuga
Jun-Ichi
J
Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Tokyo, Japan.
Nakagome
Izumi
I
Aoyama
Atsushi
A
Sako
Kumiko
K
Ishizawa
Michiyasu
M
Ogura
Michitaka
M
Makishima
Makoto
M
Hirono
Shuichi
S
Hashimoto
Yuichi
Y
Miyachi
Hiroyuki
H
D000818:Animals; D001665:Binding Sites; D002087:Butyrates / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009152:Mutagenicity Tests; D047494:PPAR delta / Q000819:agonists*; D010642:Phenoxyacetates / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; D002087:Butyrates; C110636:GW 2433; C425931:GW 501516; D006845:Hydrocarbons, Fluorinated; C522374:KCL compound; D047494:PPAR delta; D010642:Phenoxyacetates; D010671:Phenylurea Compounds; C522376:TIPP-401; D013844:Thiazoles; D015118:Eicosapentaenoic Acid