Description
Summary Abstract
BAM15 (N5,N6-Bis(2-fluorophenyl)[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine; furazano[3,4-b]pyrazine mitochondrial uncoupler; C16H10F2N6O; MW 340.29 g/mol; CAS 210302-17-3) is a cell-permeable, mitochondria-targeted protonophore uncoupler that dissipates the proton-motive force across the inner mitochondrial membrane (IMM) by shuttling protons back across the IMM independently of ATP synthase. This raises the electron transport chain (ETC) rate and fuel oxidation to compensate for reduced ATP output, producing a net increase in energy expenditure. The critical pharmacological safety advance of BAM15 over all prior uncouplers — including 2,4-dinitrophenol (DNP) and carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) — is its strict selectivity for the mitochondrial inner membrane and inability to depolarize the plasma membrane, eliminating the systemic thermogenic crisis that made classical uncouplers lethal in human use. BAM15 exhibits an EC50 of approximately 270 nM in L6 skeletal myoblast mitochondria and has an effective concentration range of 3–100 µM in cell culture models — substantially wider and safer than FCCP. In diet-induced obese (DIO) mouse models, BAM15 reversed obesity, preserved lean mass, reduced hepatic steatosis, and improved fasting glucose with no animal deaths, no hyperthermia, and no reduction in food intake at therapeutic doses, confirming mechanism-specific fat oxidation rather than anorexia as the primary efficacy driver. Secondary AMPK pathway activation (via ↑AMP:ATP ratio) drives PGC-1α-mediated mitochondrial biogenesis, adding an adaptive component to the acute fuel oxidation effect. Clinical development is in preclinical phase; no human trials have been published.
Clinical Indications
BAM15’s preclinical evidence base spans metabolic, oncological, inflammatory, and longevity applications:
- Obesity and Metabolic Syndrome (Preclinical): DIO mice treated with BAM15 showed reversal of diet-induced obesity, complete lean mass preservation, reduced hepatic steatosis, normalized fasting glucose, and improved insulin sensitivity — with no hyperthermia, no food intake reduction, and no animal deaths. Combination with a GLP-1 receptor agonist produced greater fat and liver triglyceride reduction than either agent alone, with complementary mechanism of action.
- Sepsis and Multi-Organ Failure (Preclinical): In a cecal ligation and puncture (CLP) polymicrobial sepsis model, BAM15 administered early (within 1–3 hours) improved survival from 25% to 75%. When administered at 6–12 hours post-CLP, survival benefit was maintained; BAM15 reduced serum creatinine, BUN, and hepatic markers, suggesting renal and hepatic organ protection during septic injury.
- Oncology (Preclinical): BAM15 demonstrated dose-dependent anti-proliferative activity in non-small cell lung cancer (NSCLC), breast cancer, and acute myeloid leukemia (AML) cell lines and xenograft models. The mechanism is consistent with mitochondrial membrane potential disruption selectively in metabolically hyperactive cancer cells (Warburg phenotype with mitochondrial plasticity), without cytotoxicity in normal cell lines at therapeutic concentrations.
- Longevity and Healthspan (Preclinical): BAM15 extended median lifespan by 9% in Drosophila melanogaster on standard diet and by 25% on high-fat diet, consistent with mitochondrial uncoupling hormesis. In C. elegans, lifespan extension and neuroprotection were confirmed. These findings align with the longevity benefits observed with caloric restriction and mitochondrial uncoupling across species.
Contraindications
- Thyroid Disease / Hyperthyroidism: Mitochondrial uncouplers and hyperthyroidism have overlapping physiological effects (increased thermogenesis, increased heart rate, increased oxygen consumption); combination may produce additive cardiovascular and thermogenic stress; use with caution in thyroid-active states.
- Severe Cardiac Disease / Heart Failure: Increased myocardial oxygen demand from enhanced ETC activity may be poorly tolerated in compromised cardiac function states; preclinical data show favorable cardiac effects at research doses but no human cardiac safety data exist.
- Pregnancy and Lactation: No reproductive or developmental toxicology data available; systemic effects on fetal/neonatal mitochondrial energetics are unknown; avoid use.
- Concomitant Use of Other Mitochondrial Toxins or ETC Inhibitors: Co-administration with respiratory chain inhibitors (e.g., metformin at high dose, rotenone, antimycin A) may create unpredictable and potentially catastrophic energetic imbalances by simultaneously impairing ETC electron flow while BAM15 is increasing uncoupled respiration; requires careful preclinical experimental design when combining agents.
Mechanism of Action (MOA)
BAM15 acts through a distinct and precisely characterized mitochondrial mechanism:
Protonophore Uncoupling — Plasma Membrane-Safe Proton Shuttle
BAM15 is a lipophilic weak acid that, once inside the cell, partitions into the inner mitochondrial membrane (IMM) based on its pKa properties and membrane potential. In its deprotonated (anionic) form, BAM15 migrates from the matrix-facing leaflet to the intermembrane space-facing leaflet, picks up a proton in the high-proton environment of the IMS, then shuttles back to the matrix — effectively dissipating the proton gradient without requiring ATP synthase. This raises ETC electron transport to compensate for the reduced electrochemical gradient, increasing oxygen consumption and fuel (glucose + fatty acid) oxidation. Crucially, BAM15’s molecular charge properties prevent insertion into or activity at the plasma membrane, making it mechanistically distinct from FCCP and DNP, both of which depolarize the plasma membrane and cause systemic toxicity. EC50 ~270 nM; effective research concentration range 3–100 µM; mitochondrial selectivity confirmed by cellular membrane potential studies.
Secondary AMPK Activation → Mitochondrial Biogenesis
The increased oxygen consumption and ATP demand generated by BAM15 uncoupling raises the intracellular AMP:ATP ratio, which allosterically activates AMP-activated protein kinase (AMPK). Active AMPK phosphorylates ACC to redirect acetyl-CoA from lipogenesis toward beta-oxidation, activates TFEB for lysosomal biogenesis, and upregulates PGC-1α — the master transcriptional coactivator for mitochondrial biogenesis. Over time, this produces adaptive mitochondrial expansion: increased mitochondrial density, improved oxidative capacity, and enhanced metabolic flexibility in skeletal muscle, adipose, and hepatic tissue. This biogenesis component is analogous to the adaptations seen with chronic endurance exercise training.
Adipose-Selective Biodistribution — Favorable Metabolic Targeting
Tissue distribution studies demonstrate that BAM15 achieves its highest concentrations in white adipose tissue (WAT) and brown adipose tissue (BAT), followed by liver, heart, and kidney — the primary metabolic tissues responsible for energy storage and mobilization. This biodistribution profile is favorable for obesity and MASLD applications: BAM15 preferentially accumulates where abnormal lipid storage and mitochondrial dysfunction are most clinically significant, while its short plasma half-life (~3 hours in mice) limits systemic off-target exposure. The WAT/BAT selectivity also enhances thermogenic synergy with BAT’s native UCP-1-mediated uncoupling capacity.
Anti-Inflammatory and Cytoprotective Signaling
Beyond direct energetic effects, BAM15 exerts anti-inflammatory effects relevant to its sepsis and organ protection data. Mitochondrial uncoupling reduces mitochondrial reactive oxygen species (ROS) production by preventing over-reduction of the electron transport chain — a counterintuitive protective effect of mild uncoupling. Reduced mitochondrial ROS attenuates NLRP3 inflammasome activation, NF-κB signaling, and cytokine storm amplification. In the CLP sepsis model, early BAM15 treatment prevented mitochondrial dysfunction-driven organ failure in kidney and liver, suggesting that metabolic resuscitation — rather than direct antimicrobial action — is the operative mechanism.
Key Features & Specifications
Key physicochemical and preclinical attributes of BAM15:
Chemical Analysis
| Property | Specification Reference Data |
|---|---|
| IUPAC Name | N5,N6-Bis(2-fluorophenyl)[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine |
| CAS Number | 210302-17-3 |
| Molecular Formula | C16H10F2N6O |
| Molecular Weight | 340.29 g/mol |
| Synonyms | BAM-15; BAM 15; furazano[3,4-b]pyrazine uncoupler |
| Solubility | Soluble in DMSO; poorly water-soluble; lipophilic (favors membrane partitioning) |
| Plasma Half-Life | ~3 hours (mice); clinical data pending |
| EC₅₀ (Mitochondria) | ~270 nM (L6 skeletal myoblast mitochondria) |
| Form / Variation | 50 MG Capsules (C-005) |
| Quantity | Per capsule count per bottle; see product listing |
Storage, Safety, and Handling
Storage Protocol
Store BAM15 powder or capsule formulation at −20 °C, protected from moisture and light. As a lipophilic small molecule, BAM15 is susceptible to oxidation and hydrolysis under ambient conditions. Aliquot to avoid repeat freeze-thaw cycles when working with bulk powder. DMSO stock solutions (commonly used in preclinical research) should be stored at −20 °C in tightly sealed vials; avoid aqueous dilutions above 0.1% DMSO in cell culture media for cytotoxicity control. Capsule formulations should be stored per label in a cool, dry environment.
Handling & Compliance
Handle with standard PPE (gloves, eye protection) in a well-ventilated laboratory setting. BAM15’s primary safety advantage over classical uncouplers is confirmed in extensive rodent studies: no hyperthermia, no plasma membrane depolarization, and no lethality at doses producing obesity reversal. Short plasma half-life (~3 hours in mice) limits systemic accumulation. No human pharmacokinetic, pharmacodynamic, or safety data have been published; all clinical application is pending Phase I evaluation. BAM15 is not FDA-approved for any indication and is not for human therapeutic use outside formally supervised clinical trial contexts. Regulatory status: active preclinical research compound.