BAM15 100x15mg

                                         NOT FOR HUMAN CONSUMPTION

BAM15 (N5,N6-bis(2-fluorophenyl)-1,2,5-oxadiazolo[3,4-d]pyridazine-3,6-diamine) is a recently developed mitochondrial uncoupler that has emerged as a promising agent for treating a range of conditions including obesity, metabolic syndrome, sepsis, inflammation, cancer, and age-related diseases. Unlike earlier uncouplers such as 2,4-Dinitrophenol (2,4-DNP), BAM15 selectively uncouples oxidative phosphorylation without depolarizing the plasma membrane, offering a potentially safer pharmacological profile.

2. Mechanism of Action

2.1. Mitochondrial Uncoupling

BAM15 acts by transporting protons across the inner mitochondrial membrane (IMM), bypassing ATP synthase and dissipating the proton motive force. This leads to:

• Increased substrate oxidation

• Elevated oxygen consumption

• Heat generation

• Reduced ATP production efficiency

This uncoupling leads to higher energy expenditure without triggering dangerous systemic thermogenesis observed with previous uncouplers.

2.2. Selective Targeting

BAM15 is designed to avoid depolarizing the plasma membrane, a significant safety advantage. This selectivity helps reduce cytotoxicity and systemic side effects.

3. Preclinical Applications and Efficacy

3.1. Obesity and Insulin Resistance

In mouse models of diet-induced obesity, BAM15 has demonstrated:

• Significant reductions in body weight and fat mass

• Preservation of lean mass

• Improved glucose tolerance and insulin sensitivity

• Decreased hepatic lipid accumulation

These effects occurred without a reduction in food intake, indicating increased energy expenditure as the primary mechanism.

3.2. Aging and Sarcopenic Obesity

Aging is associated with muscle atrophy and increased fat accumulation. BAM15 administration in aged rodents resulted in:

• Decreased adiposity

• Preservation of skeletal muscle mass

• Enhanced mitochondrial quality control

• Improved muscle strength and endurance

This suggests its potential role in healthy aging and prevention of frailty syndromes.

3.3. Sepsis and Systemic Inflammation

In models of polymicrobial sepsis and LPS-induced inflammation, BAM15 treatment led to:

• Lowered circulating cytokines (e.g., IL-6, TNF-α)

• Improved survival rates

• Reduced mitochondrial ROS

• Protection of renal and hepatic tissues from oxidative damage

These results support its potential as a mitochondria-targeted anti-inflammatory therapy.

3.4. Oncology

BAM15 has shown cytotoxic effects in tumor cells, particularly those reliant on mitochondrial metabolism. In preclinical cancer models:

• It disrupted oxidative phosphorylation in cancer cells

• Increased ROS production

• Induced apoptosis

• Enhanced sensitivity to chemotherapeutic agents

Applications are being investigated in acute myeloid leukemia (AML), melanoma, and triple-negative breast cancer.

4. Pharmacokinetics and Delivery Challenges

4.1. Pharmacological Properties

• BAM15 is highly lipophilic, which aids mitochondrial targeting but limits aqueous solubility.

• The compound is rapidly taken up by cells and accumulates in mitochondria.

4.2. Bioavailability and Formulation

Due to its physicochemical properties, BAM15 faces challenges in oral bioavailability. Strategies under investigation include:

• Liposomal encapsulation

• Nanoparticle carriers

• Prodrug development

• PEGylation for improved pharmacokinetics

Optimizing delivery methods is critical for clinical translation.

5. Safety and Toxicology

5.1. Preclinical Safety Profile

• BAM15 does not induce hyperthermia, unlike older uncouplers.

• No significant changes were observed in liver, kidney, or cardiac function at therapeutic doses.

• It maintains a favorable therapeutic window in rodents, with minimal off-target toxicity.

5.2. Comparative Safety Assessment

6. Regulatory Status

BAM15 remains in the preclinical development phase. As of 2025, it has not been approved by the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), or any other regulatory body.

• No registered clinical trials in humans

• Development remains at the academic and early-stage biotech level

Further toxicological profiling, formulation development, and clinical safety data will be necessary before progression to human studies.

7. Future Directions and Research Opportunities

• Metabolic Disease: As a pharmacological mimetic of caloric restriction and exercise, BAM15 may become a viable intervention for obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD).

• Longevity Research: Its role in mitochondrial quality control and oxidative stress reduction supports further exploration in aging and age-associated disease prevention.

• Combination Therapies: Potential for co-administration with metformin, rapamycin, or NAD+ precursors to synergistically target cellular energy metabolism and inflammation.

• Mitochondrial Disorders: BAM15 may offer therapeutic value in conditions characterized by mitochondrial dysfunction, pending targeted delivery strategies.

8. Conclusion

BAM15 is a novel and promising mitochondrial uncoupler with broad potential across metabolic, inflammatory, and oncological domains. By increasing energy expenditure and reducing oxidative damage without the safety liabilities of historical uncouplers, it represents a compelling candidate for therapeutic development.

Key challenges remain in drug delivery, bioavailability, and regulatory approval, but the strong foundation of preclinical efficacy and safety justifies continued investment and investigation.

Key References

1. Alexopoulos SJ, et al. Nature Communications, 2020. “BAM15 reverses diet-induced obesity and insulin resistance in mice.”

2. Tsuji N, et al. Journal of Clinical Investigation, 2023. “BAM15 mitigates sepsis-induced organ damage.”

3. Gao Z, et al. Biochemical Pharmacology, 2022. “BAM15 induces apoptosis in acute myeloid leukemia through ROS generation.”

4. Kirwan JP, et al. EMBO Molecular Medicine, 2022. “BAM15 improves glucose metabolism and mitochondrial quality in aging mice.”

5. Zunica ERM, et al. Cancer & Metabolism, 2021. “BAM15 suppresses breast cancer cell proliferation via mitochondrial targeting.”