Design, synthesis, and structure-activity relationship of carbamate-tethered aryl propanoic acids as novel PPARalpha/gamma dual agonists.
We have developed a new class of PPARalpha/gamma dual agonists, which show excellent agonistic activity in PPARalpha/gamma transactivation assay. In particular, (R)-9d was identified as a potent PPARalpha/gamma dual agonist with EC(50)s of 0.377 microM in PPARalpha and 0.136 microM in PPARgamma, respectively. Interestingly, the structure-activity relationship revealed that the stereochemistry of the identified PPARalpha/gamma dual agonists significantly affects their agonistic activities in PPARalpha than in PPARgamma.
Kim
Nam-Jung
NJ
College of Pharmacy, Seoul National University, Sillim-dong, Seoul, Republic of Korea.
Lee
Kwang-Ok
KO
Koo
Bon-Woong
BW
Li
Funan
F
Yoo
Ja-Kyung
JK
Park
Hyun-Ju
HJ
Min
Kyung-Hoon
KH
Lim
Joong In
JI
Kim
Mi Kyung
MK
Kim
Jin-Kwan
JK
Suh
Young-Ger
YG
D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011422:Propionates / Q000737:chemistry*; D000077154:Rosiglitazone; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000494:pharmacology; D015533:Transcriptional Activation
D002219:Carbamates; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D011422:Propionates; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C029658:propionic acid; D005998:Glycine; C500085:muraglitazar