PAR-1622 is a selective peroxisome proliferator-activated receptor gamma partial activator with preserved antidiabetic efficacy and broader safety profile for fluid retention.
Peroxisome proliferator-activated receptor (PPAR) gamma is known to be a key regulator of insulin resistance. PAR-1622 is a novel small molecule compound synthesized in Dong-A research center. In this study, we characterized the pharmacological profiles of PAR-1622, a selective partial activator of PPARgamma. In transient transactivation assays, PAR-1622 [(S)-2-ethoxy-3(4-(5-(4-(5-(methoxymethyl)isoxazol-3-yl)phenyl)-3-methylthiophen-2-yl)methoxy)phenyl)propanoic acid] showed a partial activator against human PPARgamma with an EC(50) of 41 nM and a maximal response of 37% relative to the full agonist rosiglitazone without activating human PPARdelta. PAR-1622 was 56 folds more selective for human PPARgamma than for human PPARalpha (EC(50), 2304 nM), which means that it is a selective partial activator of PPARgamma. PAR-1622 also showed a partial activator against mouse PPARgamma with an EC(50) of 427 nM and a maximal response was 57% of that of rosiglitazone. INT-131, a selective PPARgamma partial agonist in clinical stage, also was a partial activator against human PPARgamma with an EC(50) of 83 nM and a maximal response achieved by INT-131 was 49% of that observed with full agonist rosiglitazone. In functional assays using human mesenchymal stem cells, PAR-1622 induced adipocyte differentiation, which was 3-fold more potent with a comparable maximum response compared to INT-131. Furthermore, PAR-1622 significantly improved hyperglycemia in db/db when orally administered at a dose of 1 mg/kg/day for 5 days. In hemodilution assays with Evans Blue, rosiglitazone significantly increased the plasma volume in ICR mice that were orally administered 30 mg/kg/day for 9 days; however, PAR-1622 showed no significant effects on plasma volume, similar to INT-131. These results suggest that PAR-1622 is a selective partial activator of PPARgamma and has excellent antihyperglycemic activities and a broad safety profile for fluid retention.
Kim
Mi-Kyung
MK
Dong-A Research Center, 47-5 Sanggal-dong, Giheung-gu, Yongin-si, Gyeonggi-do, 446-905, Korea.
Chae
Yu Na
YN
Kim
Hae Sun
HS
Choi
Song-hyen
SH
Son
Moon Ho
MH
Kim
Soon Hoe
SH
Kim
Jin Kwan
JK
Moon
Ho Sang
HS
Park
Sang Kuk
SK
Shin
Young Ah
YA
Kim
Jae Gyu
JG
Lee
Chun Ho
CH
Lim
Joong In
JI
Shin
Chang Yell
CY
D050156:Adipogenesis / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001810:Blood Volume / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D017930:Genes, Reporter; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D014162:Transfection; D014882:Water-Electrolyte Balance / Q000187:drug effects*
C541580:(S)-2-ethoxy-3-(4-(5-(4-(5-(methoxymethyl)isoxazol-3-yl)phenyl)-3-methylthiophen-2-yl)methoxyphenyl)propanoic acid; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007555:Isoxazoles; D047495:PPAR gamma; D011422:Propionates; D045162:Thiazolidinediones; D013876:Thiophenes; D000077154:Rosiglitazone