SAR-oriented discovery of peroxisome proliferator-activated receptor pan agonist with a 4-adamantylphenyl group as a hydrophobic tail.
3-(4-Alkoxyphenyl)propanoic acid derivatives were prepared as candidate peroxisome proliferator-activated receptor (PPAR) alpha/delta/gamma pan agonists, based on our previous SAR studies directed toward the development of subtype-selective PPAR agonists. Those studies indicated that the steric bulkiness of substituents introduced at the distal benzene ring had an important influence on PPAR activity. The finding that a 4-adamantyl derivative exhibited not only PPARalpha/delta activity but also significant PPARgamma activity prompted us to search for structurally novel phenylpropanoic acid derivatives with more potent adipocyte differentiation activity than the well-known PPARgamma agonist, rosiglitazone, as well as well-balanced PPARalpha and PPARdelta agonistic activities. A representative phenylpropanoic acid derivative (12) bearing a 4-adamantylphenyl substituent proved to be a well-balanced PPAR-pan agonist with activities to regulate the expression of genes involved in lipid and glucose homeostasis, and should be useful as a candidate drug for the treatment of altered PPAR function.
Kasuga
Jun-ichi
J
Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Yamasaki
Daisuke
D
Ogura
Kiyoshi
K
Shimizu
Motomu
M
Sato
Mayumi
M
Makishima
Makoto
M
Doi
Takefumi
T
Hashimoto
Yuichi
Y
Miyachi
Hiroyuki
H
D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D015394:Molecular Structure; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D013329:Structure-Activity Relationship
D047492:Peroxisome Proliferator-Activated Receptors; D000218:Adamantane