Inolitazone dihydrochloride is a novel high-affinity agonist of PPARγ. It is dependent upon PPARγ for its biological activity (IC50: 0.8 nM for growth inhibition).

Inolitazone specifically activates PPARγ, but not PPARα or PPARδ. Inolitazone dihydrochloride upregulates the cell cycle kinase inhibitor, p21WAF1/CIP1. Silencing p21WAF1/CIP1 rendered cells insensitive to Inolitazone. A 10 nM dose of Inolitazone activates PPARγ: RXRα-dependent transcription as demonstrated in a transient transfection assay utilizing a PPRE response element fused to a luciferase reporter gene (PPRE3-tk-luc).The EC50s are 1 nM (Inolitazone), 65 nM (Rosiglitazone) and 631 nM (Troglitazone). Similarly, the calculated inhibitory concentration at IC50 is 0.8 nM for Inolitazone, 75 nM for Rosiglitazone, and 1412 nM for Troglitazone. Exposure of 10 nM Inolitazone following transient transfection with the appropriate PPAR isoform (γ, α, or δ) and PPAR response element linked to a luciferase reporter in RIE rat small intestinal cell line, which does not express PPARs, yields increased luciferase activity only in the presence of PPARγ and PPRE3-tk-luc[1]. DRO cells are treated in culture with Inolitazone, Rosiglitazone, or Troglitazone at the indicated concentrations. DRO cells are transiently transfected with PPRE3-tk-luc to examine effective concentrations at which EC50 occurs. DRO cells are growth inhibited by 10 nM Inolitazone (RS5444) through a PPARγ-dependent mechanism[2].

Inolitazone dihydrochloride plus Paclitaxel demonstrate additive antiproliferative activity in cell culture and minimal ATC tumor growth. Tumor growth is inhibited in a dose-responsive fashion when Inolitazone is administered in the diet to athymic nude mice prior to DRO tumor cell implantation. Tumors are nest allowed to establish in the mouse and began 0.025% Inolitazone treatment of mice 1 week after DRO or ARO tumor cell implantation. Inolitazone treated animals demonstrate tumor growth inhibition of 68.9% in DRO tumors and 48.3% in ARO tumors as compared to that of their respective controls on day 35. At the highest dose, 0.025% Inolitazone inhibits growth on day 32 by 94.4% as compared to that of control. Five of 10 animals do not develop demonstrable tumors, in this treatment group. Tumor growth is inhibited by 62.3% compared to that of control on day 32 while the 0.00025% dose demonstrated no growth inhibitory activity as compared to control, in the 0.0025% treatment group[1].

223132-38-5

C27H28Cl2N4O4S

575.51

CS-7017 dihydrochloride;Efatutazone dihydrochloride;RS5444 dihydrochloride;Inolitazone dihydrochloride

DMSO:25 mg/mL (43.44 mM),Need ultrasonic
Powder: -20°C for 3 years
In solvent: -80°C for 2 years