title: NS-1: a novel partial peroxisome proliferator-activated receptor γ agonist to improve insulin sensitivity and metabolic profile.
abstract: Peroxisome proliferator-activated receptor (PPAR) γ is known to be a key regulator of insulin resistance. We characterized the pharmacological profiles of NS-1 chemically known as (5Z)-5-[4-hydroxy-3-methoxy-phenyl) methylene] thiazolidine-2, 4-dione), as a selective partial activator of PPARγ. In transient transactivation assay in NIH3T3 cells, NS-1 showed a partial activation against human PPARγ with an EC (50) of 0.91 μM without activating human PPARα and PPARδ. In adipocyte differentiation assay, NS-1 induced adipocyte differentiation, which was ~25-fold weaker inducer of GPDH activities than pioglitazone and also showed weak adipogenic activity in C3H10T1/2 pluripotent stem cells using Oil Red O staining. NS-1 showed good in vivo pharmacokinetic profiles in C57BL/6J mice at 30 mg/kg oral dose with Cmax-26 μM, terminal elimination half-life- 2.5h and bioavailability of 85%. Furthermore, NS-1 significantly improved hyperglycemia and insulin resistance in DIO animals when orally administered at a dose of 30 mg/kg/day for 45 days without significant weight gain. Overall, these studies suggest that NS-1 improves insulin resistance in such animal models through activation of PPARγ-mediated transcriptional activity and that it would be a new therapeutic candidate with potential for the treatment of type 2 diabetic patients.
authors.affiliation: Department of Pharmacology, Faculty of pharmacy, Shri Neminath Jain Bramhacharyashram's Shriman Sureshdada Jain college of pharmacy Jain gurukul, Chandwad, Nashik, India.
authors.forename: Sumit
authors.initials: S
authors.lastname: Chaudhary
authors.forename: Aakanksha
authors.initials: A
authors.lastname: Dube
authors.forename: Vishal
authors.initials: V
authors.lastname: Kothari
authors.forename: Narsingh
authors.initials: N
authors.lastname: Sachan
authors.forename: Chandrashekhar Devidas
authors.initials: CD
authors.lastname: Upasani
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D053778:Thiazolidines / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C574780:((5Z)-5-(4-hydroxy-3-methoxy-phenyl)methylene)thiazolidine-2,4-dione; D047495:PPAR gamma; D045162:Thiazolidinediones; D053778:Thiazolidines; D000077205:Pioglitazone