title: Design, synthesis, and biological evaluation of novel constrained meta-substituted phenyl propanoic acids as peroxisome proliferator-activated receptor alpha and gamma dual agonists.
abstract: 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.
authors.affiliation: College of Pharmacy, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul 151-742, South Korea. ygsuh@snu.ac.kr
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
authors.forename: Nam-Jung
authors.initials: NJ
authors.lastname: Kim
authors.forename: Bon-Woong
authors.initials: BW
authors.lastname: Koo
authors.forename: Kwang-Ok
authors.initials: KO
authors.lastname: Lee
authors.forename: Sung-Hyun
authors.initials: SH
authors.lastname: Moon
authors.forename: Dong-Hyung
authors.initials: DH
authors.lastname: Shin
authors.forename: Jong-Wha
authors.initials: JW
authors.lastname: Jung
authors.forename: Seung-Mann
authors.initials: SM
authors.lastname: Paek
authors.forename: Dong-Jo
authors.initials: DJ
authors.lastname: Chang
authors.forename: Funan
authors.initials: F
authors.lastname: Li
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Tuong Vy Thi
authors.initials: TV
authors.lastname: Le
authors.forename: Yu Na
authors.initials: YN
authors.lastname: Chae
authors.forename: Chang Yell
authors.initials: CY
authors.lastname: Shin
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Kim
authors.forename: Joong In
authors.initials: JI
authors.lastname: Lim
authors.forename: Jae-Sang
authors.initials: JS
authors.lastname: Ryu
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
mesh_terms: 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
chemical_list: D007555:Isoxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates