BAM-15 50 mg – 60 capsules

BAM-15 50 mg — 60 oral research capsules. BAM-15 is the most pharmacologically refined mitochondrial protonophore uncoupler ever developed — and the first such molecule with a meaningful safety margin over the historical leader 2,4-dinitrophenol (DNP). Identified in a chemical screen by the Hoehn group at the University of Sydney (Kenwood et al., Mol Metab 2014), BAM-15 selectively depolarizes the mitochondrial inner membrane without affecting the plasma membrane — the mechanistic distinction that eliminates the cardiovascular and thermogenic toxicity that has limited every prior uncoupler. In landmark 2020 work by Axelrod et al. (EMBO Mol Med), BAM-15 prevented diet-induced obesity and improved glycemic control in mice without behavioral or temperature toxicity, repositioning mitochondrial uncoupling as a credible therapeutic strategy for metabolic disease.

Research Overview

BAM-15 (N5,N6-bis(2-fluorophenyl)[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine) is a furazano-pyrazine protonophore that selectively shuttles protons across the mitochondrial inner membrane, dissipating the electrochemical gradient that drives ATP synthase and accelerating substrate oxidation through the electron transport chain [1]. In contrast to the historical reference compound DNP, BAM-15 does not depolarize the plasma membrane — a property attributable to its specific physicochemical profile and one that abolishes the cardiovascular toxicity (tachycardia, hyperthermia, sudden death) that ended DNP’s clinical use in the 1930s [1,2]. In the 2020 Axelrod et al. study, oral BAM-15 administered to diet-induced-obese mice produced robust weight loss and dramatic improvements in insulin sensitivity, glucose tolerance and hepatic steatosis without affecting food intake, body temperature or activity — clean separation from the toxicity profile of every prior uncoupler [2]. Subsequent work has demonstrated activity in models of acute kidney injury, sepsis, breast cancer proliferation and aging-related neurodegeneration in C. elegans (lifespan extension) [3]. BAM-15 is now the most clinically translatable mitochondrial uncoupler in the published literature.

Primary Research Areas

• Mitochondrial uncoupling pharmacology — the cleanest and most mitochondria-selective protonophore in the published literature, superseding DNP, FCCP and CCCP for in-vivo mechanistic work [1,2].
• Obesity and metabolic disease — robust weight-loss and glycemic-improvement signals in DIO mouse models with no thermogenic or cardiovascular toxicity, clearly differentiated from DNP [2].
• Renal ischemia-reperfusion and AKI — protective in cold-storage, ischemic and septic acute kidney injury models, with mtROS reduction as a proximate mechanism [3].
• Cancer metabolism research — investigated in TNBC and other proliferation-driven tumor models where mitochondrial vulnerability provides a targetable axis [3].
• Aging and longevity — extends lifespan and rescues neurodegenerative phenotypes in C. elegans, providing a tractable invertebrate model of mitochondrial-uncoupling-driven longevity [3].

References

1. Kenwood BM, Weaver JL, Bajwa A, et al. Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane. Mol Metab. 2014;3(2):114–123.
2. Axelrod CL, King WT, Davuluri G, et al. BAM15-mediated mitochondrial uncoupling protects against obesity and improves glycemic control. EMBO Mol Med. 2020;12(7):e12088.
3. Alexopoulos SJ, Chen SY, Brandon AE, et al. Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice. Nat Commun. 2020;11(1):2397.