PAR-5359, a well-balanced PPARalpha/gamma dual agonist, exhibits equivalent antidiabetic and hypolipidemic activities in vitro and in vivo.
Peroxisome proliferator-activated receptor (PPAR) alpha and gamma are key regulators of lipid homeostasis and insulin resistance. In this study, we characterize the pharmacological profiles of PAR-5359, a dual agonist of PPARalpha and gamma with well-balanced activities. In transient transactivation assay, PAR-5359 (3-(4-(2[4-(4chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethoxy)-phenyl)-(2S)-ethoxy-propionic acid) significantly activated human and mouse PPARalpha and gamma without activating PPARdelta. In functional assays using human mesenchymal stem cells and human hepatoma HepG2 cells, PAR-5359 significantly induced adipocyte differentiation and human ApoA1 secretion, which coincided with its transactivation potencies against the corresponding human receptor subtypes. Interestingly, PAR-5359 showed equivalent potencies against the mouse receptor subtypes (alpha and gamma; 2.84 microM and 3.02 microM, respectively), which suggests the possibility that PAR-5359 could simultaneously activates each subtype of receptors subtype in under physiological conditions. In an insulin-resistant ob/ob mouse model, PAR-5359 significantly reduced plasma insulin levels, improved insulin sensitivity (HOMA-IR), and completely normalized plasma glucose levels. In a severe diabetic db/db mouse model, PAR-5359 dose-dependently reduced the plasma levels of glucose (ED(30) = 0.07 mg/kg). Furthermore, it lowered plasma levels of non HDL- (ED(30) = 0.13 mg/kg) and total cholesterol (ED(30) = 0.03 mg/kg) in high cholesterol diet-fed rats for 4 days treatment. These results suggest that PAR-5359 has the balanced activities for PPARalpha and PPARgamma in vivo as well as in vitro. And its balanced activities may render PAR-5359 as a pharmacological tool in elucidating the complex roles of PPARalpha/gamma dual agonists.
Kim
Mi-Kyung
MK
Research Center, Dong-A Pharm. Co., Ltd., Sanggal-dong, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.
Chae
Yu Na
YN
Son
Moon Ho
MH
Kim
Soon Hoe
SH
Kim
Jin Kwan
JK
Moon
Ho Sang
HS
Park
Chan Sun
CS
Bae
Myung-Ho
MH
Kim
Eunkyung
E
Han
Taedong
T
Choi
Hyun-Ho
HH
Shin
Young Ah
YA
Ahn
Byung-Nak
BN
Lee
Chun Ho
CH
Lim
Joong In
JI
Shin
Chang Yell
CY
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000819:agonists; D013997:Time Factors
C532944:(3-(4-(2(4-(4chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl)-ethoxy)-phenyl)-(2S)-ethoxy-propionic acid); D016632:Apolipoprotein A-I; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007328:Insulin; D047493:PPAR alpha; D047495:PPAR gamma; D011422:Propionates; D011725:Pyridines; D011993:Recombinant Fusion Proteins