A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss

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 .

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Publication Details

Journal
Nature Metabolism
Published
2025-06-17
DOI
https://doi.org/10.1038/s42255-025-01311-z
Citations
9
Primary Topic
Adipose Tissue and Metabolism
Type
article
Field-Weighted Citation Impact
10.48
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article

A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss

Alejandro Leyva, Williams Porcal, Shailendra Giri, John M. Hollander et al.
9 citations
Nature Metabolism
Adipose Tissue and Metabolism
10.48
article

A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss

Alejandro Leyva, Williams Porcal, Shailendra Giri, John M. Hollander, Jacqueline Haag, Ethan Meadows, Victoria de la Sovera, Gleyce Moreno Barbosa, Mariana Ingold, Marina Santos Chichierchio, Mariana Bresque, Santiago Ruiz, Graham P. Holloway, R Leonardi, Lucía Colella, Aldo Calliari, Jorge Rodriguez‐Duarte, Marcelo A. Mori, Rosina Dapueto, João Manoel Alves, Peter Breining, Paola Contreras, Gloria V. López, William T. Festuccia, Guillermo Moyna, José Manuel Verdes, Andrés Kamaid, Karina Cal, Robert M. O’Doherty, María Pía Garat, Rosario Durán, Larissa Menezes dos Reis, Eduardo N. Chini, Guillermo Agorrody, Sara E. Lewis, Jianhai Du, Thomas A. White, Rachel D. King, Camila Espasandín, Andrés López, Luiz Osório Leiria, Andrés Benítez-Rosendo, Thayna S. Vieira, Mikkel Holm Vendelbo, Carlos Batthyány, Lucía Ziegler, Carlos Escande, Adrián Aicardo, Valentina Pérez-Torrado, Valeria Valez, Rafael Radí, Rachel Handy, Celia Quijano, Ramandeep Rattan, Pedro M. Moraes‐Vieira, Germán Galliussi, Caroline Antunes Lino, Thais Peclat, Leonardo Santos, Juliana Camacho-Pereira, Katie L. Thompson, Cecilia Vilaseca, Yekai Wang, Eric E. Kelley, Evan DeVallance, Steen Jakobsen, Leonardo Osbourne Lai de Souza, Julia V França
article en
9 citations

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 .

Nature MetabolismVol. 7(8)
West Virginia University (US), Henry Ford Health System (US), University of Pittsburgh (US), Universidade de São Paulo (BR), Universidad de la República de Uruguay (UY), Universidade Estadual de Campinas (UNICAMP) (BR), Aarhus University (DK), Wilmington University (US), Jacksonville College (US), Aarhus University Hospital (DK), WinnMed (US), West Virginia University Hospitals (US), Universidad Nacional del Litoral (AR), Czech Academy of Sciences, Institute of Biophysics (CZ), BioEnergetics (United States) (US), Universidad CLAEH (UY), Instituto Nacional de Desenvolvimento das Pescas (CV), Mayo Clinic in Florida (US), Hospital de Clínicas (UY), Institut Pasteur de Montevideo (UY), Clinics Hospital of Ribeirão Preto (BR), Centro Uruguayo de Imagenología Molecular (UY), Universidad de Montevideo (UY), University of Guelph (CA)
Zero hunger
Openalex Percentile: Top 2%
Adipose Tissue and Metabolism
10.48
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