SRT-2379

SRT2379 is a selective small-molecule activator of sirtuin 1 (SIRT1), the NAD-dependent protein deacetylase that regulates cellular metabolism, inflammation, stress resistance, and aging-associated pathways through deacetylation of transcription factors and cofactors including p53, NF-kappaB p65, FOXO family members, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha). The compound was developed by Sirtris Pharmaceuticals, a biotechnology company founded in 2004 to translate the sirtuin biology pioneered by David Sinclair and colleagues into therapeutic agents, and was advanced into clinical development following the acquisition of Sirtris by GlaxoSmithKline in 2008 for approximately 720 million United States dollars. SRT2379 belongs to the second generation of synthetic sirtuin-activating compounds (STACs), structurally unrelated to the polyphenolic first-generation activator resveratrol and designed for improved potency, selectivity, and drug-like properties. The precise chemical structure of SRT2379 has not been publicly disclosed; related compounds in the Sirtris STAC pipeline (SRT1720, SRT2104) are based on imidazo[1,2-b]thiazole scaffolds, and SRT2379 is understood to belong to the same or a closely related chemotype.

Preclinical evaluation of SRT2379 demonstrated broad anti-inflammatory and insulin-sensitizing activity. In Zucker fatty rats, oral administration at 100 mg/kg for four weeks produced a 154 percent increase in glucose infusion rate during hyperinsulinemic-euglycemic clamp, reduced adipocyte size, shifted adipose tissue macrophage polarization away from proinflammatory CD11c-positive phenotypes, and suppressed expression of tumor necrosis factor alpha, interleukin 6, and monocyte chemoattractant protein 1 in adipose tissue [1]. In murine lipopolysaccharide (LPS) challenge models, SRT2379 suppressed systemic inflammatory cytokine release through SIRT1-mediated deacetylation of the NF-kappaB p65 subunit. These preclinical findings positioned SRT2379 as a development candidate for type 2 diabetes and inflammatory diseases.

Two Phase 1 clinical trials evaluated SRT2379 in healthy human volunteers. The first-in-human dose-escalation study (NCT01018628, EudraCT 2009-014797-17) assessed safety, tolerability, and pharmacokinetics at oral doses ranging from 25 to 3000 mg in approximately 64 healthy male subjects across eight cohorts, with fibroblast growth factor 21 (FGF21) as a pharmacodynamic biomarker. Pharmacokinetic exposures increased in a dose-dependent manner, and the compound was well tolerated across all dose levels. The second study (NCT01262911, EUDRACT 2011-002266-20, GSK trial 115830), a single-blind, placebo-controlled endotoxemia challenge in 39 healthy male subjects aged 18 to 35 years, administered single oral doses of 50, 250, or 1000 mg followed by intravenous LPS four hours later. SRT2379 did not significantly reduce release of tumor necrosis factor alpha, interleukin 6, interleukin 8, interleukin 10, or interleukin 17 compared with placebo (all comparisons P greater than 0.05), and had no measurable impact on vital signs, leukocyte counts, or coagulation activation markers [2]. The failure to translate the robust preclinical anti-inflammatory signal into measurable human pharmacodynamic activity, attributed to insufficient potency or systemic exposure at the tested doses, led to termination of SRT2379 from further clinical development. The compound is no longer in active pharmaceutical development and is not registered as a medicine in any jurisdiction. It is available as a research-grade preparation for in vitro and in vivo investigation of SIRT1 biology, metabolic regulation, and inflammatory signaling.