A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss
Recommended Citation
Cal K, Leyva A, Rodríguez-Duarte J, Ruiz S, Santos L, Garat MP, Colella L, Ingold M, Benitez-Rosendo A, Pérez-Torrado V, Vilaseca C, Galliussi G, Ziegler L, Peclat TR, Bresque M, Handy RM, King R, Menezes Dos Reis L, Alves JM, Espasandín C, de la Sovera V, Breining P, Dapueto R, Lopez A, Thompson KL, Lino CA, França JV, Vieira TS, Rattan R, Agorrody G, DeVallance E, Haag J, Meadows E, Lewis SE, Santana Barbosa GC, Lai de Souza LO, Chichierchio MS, Valez V, Aicardo A, Contreras P, Vendelbo MH, Jakobsen S, Kamaid A, Porcal W, Calliari A, Verdes JM, Du J, Wang Y, Hollander JM, White TA, Radi R, Moyna G, Quijano C, O'Doherty R, Moraes-Vieira P, Giri S, Holloway GP, Festuccia WT, Leiria LO, Leonardi R, Mori MA, Camacho-Pereira J, Kelley EE, Duran R, López GV, Chini EN, Batthyány C, and Escande C. A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss. Nat Metab 2025.
Document Type
Article
Publication Date
6-17-2025
Publication Title
Nat Metab
Abstract
The emergence of glucagon-like peptide-1 agonists represents a notable advancement in the pharmacological treatment of obesity, yet complementary approaches are essential. Through phenotypic drug discovery, we developed promising nitroalkene-containing small molecules for obesity-related metabolic dysfunctions. Here, we present SANA, a nitroalkene derivative of salicylate, demonstrating notable efficacy in preclinical models of diet-induced obesity. SANA reduces liver steatosis and insulin resistance by enhancing mitochondrial respiration and increasing creatine-dependent energy expenditure in adipose tissue, functioning effectively in thermoneutral conditions and independently of uncoupling protein 1 and AMPK activity. Finally, we conducted a randomized, double-blind, placebo-controlled phase 1A/B clinical trial, which consisted of two parts, each with four arms: (A) single ascending doses (200-800 mg) in healthy lean volunteers; (B) multiple ascending doses (200-400 mg per day for 15 days) in healthy volunteers with overweight or obesity. The primary endpoint assessed safety and tolerability. Secondary and exploratory endpoints included pharmacokinetics, tolerability, body weight and metabolic markers. SANA shows good safety and tolerability, and demonstrates beneficial effects on body weight and glucose management within 2 weeks of treatment. Overall, SANA appears to be a first-in-class activator of creatine-dependent energy expenditure and thermogenesis, highlighting its potential as a therapeutic candidate for 'diabesity'. Australian New Zealand Clinical Trials Registry registration: ACTRN12622001519741 .
Medical Subject Headings
Humans; Male; Double-Blind Method; Adult; *Thermogenesis/drug effects; *Creatine/metabolism; Female; *Weight Loss/drug effects; Obesity/drug therapy/metabolism; *Salicylates/pharmacology/chemistry/therapeutic use; Middle Aged; Energy Metabolism/drug effects; Animals; Insulin Resistance; *Alkenes/chemistry/pharmacology
PubMed ID
40527924
ePublication
ePub ahead of print
Volume
7
Issue
8
First Page
1550
Last Page
1569
