Introduction and Objective: Obesity presents a major global health concern with increasing prevalence worldwide. Currently, GLP-1 based therapies present the most effective treatment for obesity, but their tolerability and efficacy are limited by gastrointestinal side effects and compensatory reduction in energy expenditure (EE). Mitochondrial uncoupling by protonophores was shown to increase EE and reduce body weight in preclinical models and humans. However, systemic uncoupling causes severe side effects, limiting their clinical development. Restricting uncoupling activity to specific tissues therefore presents a potential strategy to improve the safety profile. Here, we report the discovery and characterization of the mitochondrial uncoupler BI-4659.Methods: Mitochondrial membrane potential and oxygen consumption rate was analyzed in HepG2 cells using the JC-10 assay and Seahorse XF analyzer, respectively. In vivo efficacy studies were conducted in diet-induced obese (DIO) mice, fed a high-fat diet (HFD). Indirect calorimetry was measured in Promethion (Sable Systems) and temperature measurements were performed using telemetry.Results:In vitro, BI-4659 modulates mitochondrial membrane potential and stimulates mitochondrial respiration with higher potency than DNP or FCCP. A persistent enrichment of BI-4659 in adipose tissue was observed in lean and DIO mice. Daily treatment of DIO mice over 5 days increases energy expenditure and reduces body weight at lower doses than the uncoupler BAM15, concomitant with an increase in body temperature. Significant prevention of body weight gain, increase in EE and only a minimal increase in body temperature was achieved by reducing dosing frequency.Conclusion: The mitochondrial uncoupler BI-4659 reverses diet-induced obesity in mice and enables an improved safety profile due to its pharmacokinetic properties and enrichment in adipose tissue.
M. Pereira: Employee; Boehringer-Ingelheim. T. Jelenik: Employee; Boehringer-Ingelheim. M. Beilmann: None. C. Braun: Employee; Boehringer-Ingelheim. M. Eckhardt: None. S. Frankenreiter: Employee; Boehringer-Ingelheim. F. Meier: None. W. Rist: Employee; Boehringer-Ingelheim. H. Saminathan: None. C. Schmid-Wiedemann: Employee; Boehringer-Ingelheim. P. Sieger: Employee; Boehringer-Ingelheim. B.E. Stierstorfer: None. L. Wortmann: Employee; Boehringer-Ingelheim. A. Pekcec: Employee; Boehringer-Ingelheim. B. Hamilton: Employee; Boehringer-Ingelheim. D.F. Markgraf: Employee; Boehringer Ingelheim Pharma GmbH & Co KG.
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