NS-1: a novel partial peroxisome proliferator-activated receptor γ agonist to improve insulin sensitivity and metabolic profile.

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.