title: PAR-1622 is a selective peroxisome proliferator-activated receptor gamma partial activator with preserved antidiabetic efficacy and broader safety profile for fluid retention.
abstract: 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.
authors.affiliation: Dong-A Research Center, 47-5 Sanggal-dong, Giheung-gu, Yongin-si, Gyeonggi-do, 446-905, Korea.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Kim
authors.forename: Yu Na
authors.initials: YN
authors.lastname: Chae
authors.forename: Hae Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Song-hyen
authors.initials: SH
authors.lastname: Choi
authors.forename: Moon Ho
authors.initials: MH
authors.lastname: Son
authors.forename: Soon Hoe
authors.initials: SH
authors.lastname: Kim
authors.forename: Jin Kwan
authors.initials: JK
authors.lastname: Kim
authors.forename: Ho Sang
authors.initials: HS
authors.lastname: Moon
authors.forename: Sang Kuk
authors.initials: SK
authors.lastname: Park
authors.forename: Young Ah
authors.initials: YA
authors.lastname: Shin
authors.forename: Jae Gyu
authors.initials: JG
authors.lastname: Kim
authors.forename: Chun Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Joong In
authors.initials: JI
authors.lastname: Lim
authors.forename: Chang Yell
authors.initials: CY
authors.lastname: Shin
mesh_terms: 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*
chemical_list: 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