N-[2-[3-(1-Piperazinylmethyl)imidazo[2,1-b]thiazol-6-yl]phenyl]-2-quinoxalinecarboxamide hydrochloride

Sirtuins (SIRTs) represent a distinct class of trichostatin A-insensitive lysyl-deacetylases (class III HDACs). Human SIRT1 is the homolog of yeast silent information regulator 2 (Sir2) and has been shown to regulate the activity of the p53 tumor suppressor and inhibit apoptosis. Small molecule activators of SIRT1, such as resveratrol, extend lifespan in yeast and C. elegans in a manner that resembles caloric restriction. SRT 1720 is a selective small molecule activator of SIRT1 that is 1,000-fold more potent than resveratrol (EC1.5 = 0.16 versus 46.2 µM, respectively). In diet-induced obese and diabetic leptin-deficient ob/ob mice, oral administration of 100 mg/kg SRT1720 once daily improves insulin sensitivity, lowers plasma glucose and increases mitochondrial capacity after one week of treatment. In Zucker fa/fa rats, SRT 1720 improves whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle, and liver.
SRT1720 hydrochloride is a selective activator of human SIRT1 (EC1.5 = 0.16 μM) versus the closest sirtuin homologues, SIRT2 and SIRT3 (SIRT2: EC1.5 = 37 μM；SIRT3: EC1.5 > 300 μM). IC50 Value: 0.16 μM(EC1.5 for SIRT1)Target: SIRT1SRT 1720 binds to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, SRT1720 improved insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. Thus, SRT1720 is a promising new therapeutic agent for treating diseases of ageing such as type 2 diabetes.