BAM15
[CAS# 210302-17-3]

Identification

• Classification: API >> Inhibitor drug
• Name: BAM15
• Synonyms: N5,N6-bis(2-Fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine
• Molecular Formula: C₁₆H₁₀F₂N₆O
• Molecular Weight: 340.29
• CAS Registry Number: 210302-17-3
• EC Number: 998-894-9
• SMILES: C1=CC=C(C(=C1)NC2=NC3=NON=C3N=C2NC4=CC=CC=C4F)F

Properties

• Solubility: 6.51 mg/L (25 ºC water)
• Density: 1.5±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.728, Calc.^*
• Melting point: 196.41 ºC
• Boiling Point: 421.7±55.0 ºC (760 mmHg), Calc.^*, 465.34 ºC
• Flash Point: 208.9±31.5 ºC, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07;GHS08;GHS09 Danger
• Hazard Statements: H302-H361-H372-H410
• Precautionary Statements: P201-P264-P280-P301+P330+P331-P312

Discovory and Applicatios

BAM15 is a synthetic chemical compound known primarily as a mitochondrial protonophore uncoupler. It has attracted attention in biomedical research for its ability to dissipate the mitochondrial proton gradient without inducing cytotoxicity at low concentrations. The molecular structure of BAM15 allows it to shuttle protons across the inner mitochondrial membrane, thereby uncoupling oxidative phosphorylation from ATP production. This unique mechanism has been studied in the context of metabolic regulation, obesity treatment, and inflammation.

BAM15 was first reported in the scientific literature in 2014 as part of efforts to identify mitochondrial-targeted uncouplers with improved pharmacological properties. Traditional uncouplers such as 2,4-dinitrophenol (DNP) are effective at increasing energy expenditure but are associated with severe toxicity. BAM15 was designed to overcome these limitations by selectively targeting mitochondria and reducing the proton motive force without significantly impairing mitochondrial membrane potential or causing systemic toxicity at moderate doses.

In animal studies, BAM15 has demonstrated the ability to increase energy expenditure, reduce body weight, and improve insulin sensitivity in models of diet-induced obesity. These effects are attributed to enhanced mitochondrial respiration and fatty acid oxidation resulting from uncoupling. Importantly, unlike earlier uncouplers, BAM15 does not appear to significantly increase body temperature, which has been a major safety concern with compounds like DNP.

BAM15 has also been studied for its potential anti-inflammatory effects. By modulating mitochondrial function and reducing the production of reactive oxygen species (ROS), BAM15 may attenuate inflammatory signaling pathways. Preclinical studies suggest that it can protect against tissue damage in models of sepsis and acute kidney injury by preserving mitochondrial function and reducing oxidative stress.

In cancer research, BAM15 has been evaluated for its ability to disrupt mitochondrial metabolism in tumor cells. Since many cancer cells rely heavily on mitochondrial bioenergetics and redox balance, BAM15-induced uncoupling may impair their proliferation and survival. However, such applications remain experimental, and further research is needed to assess selectivity, efficacy, and safety in clinical contexts.

Pharmacologically, BAM15 exhibits favorable absorption and distribution in preclinical models. It is orally bioavailable and shows mitochondrial selectivity without significantly affecting plasma membrane potential. The compound is structurally characterized by a benzimidazole moiety and specific functional groups that contribute to its protonophoric activity. Its exact metabolic and excretion pathways are still under investigation.

While BAM15 is not approved for therapeutic use and remains in the experimental stage, its unique properties have made it a valuable tool in the study of mitochondrial bioenergetics and a promising lead compound for the development of safer mitochondrial uncouplers. Its use in laboratory research continues to provide insights into mitochondrial function, energy metabolism, and disease pathophysiology.

In summary, BAM15 is a synthetic mitochondrial uncoupler discovered through rational design to overcome the toxicity of earlier compounds. It is under investigation for its ability to promote energy expenditure, reduce inflammation, and modulate mitochondrial function in various disease models, representing a novel direction in metabolic and mitochondrial-targeted therapy research.

References

2023. Oxadiazolopyridine Derivatives as Efficacious Mitochondrial Uncouplers in the Prevention of Diet-Induced Obesity. Journal of Medicinal Chemistry, 66(5).
DOI: 10.1021/acs.jmedchem.2c01573

2022. Conversion of oxadiazolo[3,4-b]pyrazines to imidazo[4,5-b]pyrazines via a tandem reduction-cyclization sequence generates new mitochondrial uncouplers. Bioorganic & Medicinal Chemistry Letters, 74.
DOI: 10.1016/j.bmcl.2022.128912

2021. Breast cancer growth and proliferation is suppressed by the mitochondrial targeted furazano[3,4-b]pyrazine BAM15. Cancer & Metabolism, 9(1).
DOI: 10.1186/s40170-021-00274-5