Design, synthesis, and biological evaluation of novel constrained meta-substituted phenyl propanoic acids as peroxisome proliferator-activated receptor alpha and gamma dual agonists.
In an effort to develop dual PPARalpha/gamma activators with improved therapeutic efficacy, a series of diaryl alpha-ethoxy propanoic acid compounds comprising two aryl groups linked by rigid oxime ether or isoxazoline ring were designed and synthesized and their biological activities were examined. Most of the compounds possessing an oxime ether linker were more potent PPARgamma activators than the lead PPARalpha/gamma dual agonist, tesaglitazar in vitro. Compound 18, one of the derivatives with an oxime ether linker, was found to selectively transactivate PPARgamma (EC 50 = 0.028 microM) over PPARalpha (EC 50 = 7.22 microM) in vitro and lower blood glucose in db/ db mice more than muraglitazar after oral treatment for 11 days.
Suh
Young-Ger
YG
College of Pharmacy, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul 151-742, South Korea. ygsuh@snu.ac.kr
Kim
Nam-Jung
NJ
Koo
Bon-Woong
BW
Lee
Kwang-Ok
KO
Moon
Sung-Hyun
SH
Shin
Dong-Hyung
DH
Jung
Jong-Wha
JW
Paek
Seung-Mann
SM
Chang
Dong-Jo
DJ
Li
Funan
F
Kang
Hyun-Jin
HJ
Le
Tuong Vy Thi
TV
Chae
Yu Na
YN
Shin
Chang Yell
CY
Kim
Mi-Kyung
MK
Lim
Joong In
JI
Ryu
Jae-Sang
JS
Park
Hyun-Ju
HJ
D000818:Animals; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
D007555:Isoxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates