New Generation of Mitochondrial Uncouplers for the Treatment of Metabolic DIsorders

Summary Effective treatments for obesity have been a major need for decades, as the high prevalence of obesity and associated metabolic disorders has continued to rise. To achieve weight loss, obesity treatments must either decrease energy intake or increase energy expenditure. GLP-1 receptor agonists have recently emerged as the first effective drugs that decrease energy intake by reducing appetite. While these drugs are promising, the need for alternative and complimentary treatments persists due to reported variations in their efficacy and suboptimal effects on body composition. Equator Therapeutics is developing a first-in-class drug to increase energy expenditure. Specialized thermogenic reactions within mitochondria form the only known energy expenditure pathway that can be safely controlled without negatively impacting other essential physiological processes. Mitochondrial thermogenesis depends on H+ leak across the inner mitochondrial membrane mediated by mitochondrial uncoupling proteins (UCPs). In vivo, UCPs are activated by long-chain fatty acids (LCFAs). In humans, skeletal muscle plays a dominant role in adaptive non-shivering thermogenesis. The UCP responsible for mitochondrial thermogenesis in skeletal muscle and its pharmacological control long remained elusive until Equator’s scientific co-founders developed a method to directly measure mitochondrial H+ leak using the patch-clamp technique and demonstrated that the LCFA-induced H+ leak in skeletal muscle is mediated by the mitochondrial ADP/ATP carrier (AAC) (Bertholet et al, Nature 2019). They also identified likely AAC binding sites for LCFAs and small-molecule activators of H+ leak (Bertholet et al, Nature 2022). Based on this work, we are developing small-molecule activators of H+ leak via AAC that mimic the thermogenic effect of LCFAs but offer high oral bioavailability. In the Phase 1 SBIR, we developed a high-throughput drug discovery funnel and identified four chemically unique lead molecules that selectively activate H+ leak via AAC. We also demonstrated that one of our partially optimized compounds can increase energy expenditure and cause weight loss in diet-induced obesity (DIO) mice. In this Phase 2 application, we propose to carry out further medicinal chemistry optimization of these lead compounds and to test optimized analogs for efficacy and safety in DIO rodent models. The proposal has three specific aims. In Aim 1 we will optimize our compounds to increase in vivo potency and maintain good exposures with chronic dosing. The optimized lead compounds will then be advanced to in vivo efficacy studies in Aim 2, where we will demonstrate that they increase the metabolic rate in DIO rodent models and determine safe doses for use in subsequent weight-loss studies. Finally, in Aim 3, we will determine the efficacy of the optimized lead compounds for treating obesity, type 2 diabetes, and fatty liver disease in DIO rodents. Successful completion of this proposal will demonstrate efficacy of our compounds in disease models and assess potential liabilities in preparation for IND-enabling studies.