5-Amino-1-MQ 100x50mg

                                             NOT FOR HUMAN CONSUMPTION

5-Amino-1MQ is a small-molecule nicotinamide N-methyltransferase (NNMT) inhibitor of the quinolinium class (often used as its water-soluble salt). NNMT catalyzes the SAM-dependent methylation of nicotinamide (NAM) → 1-methylnicotinamide (1-MNA). Inhibiting NNMT conserves cellular SAM, reduces 1-MNA formation, and redirects NAM into the NAD⁺ salvage pathway, thereby raising NAD⁺ and modulating epigenetic methylation status (the “methylation sink” concept). In adipose and liver, this re-wiring has shown anti-obesity and insulin-sensitizing effects in animals. 5-Amino-1MQ is a tool compound—it is not FDA/EMA-approved for any human indication.

Additional Benefits of 5-Amino-1MQ Now Under Investigation

2. Molecular Mechanism of Action

2.1 Target Pharmacodynamics

• Primary target: NNMT (cytosolic), which consumes S-adenosyl-methionine (SAM) to methylate nicotinamide → 1-MNA.

• Inhibition effects:

  1. ↑ NAD⁺ salvage (NAM → NMN → NAD⁺), boosting sirtuin/oxidative metabolism;

  2. ↑ SAM availability / restored methylation capacity, affecting chromatin and gene expression;

  3. ↓ 1-MNA, altering redox and signalling niches where 1-MNA is active.

2.2 Down-stream Biology

3. Pharmacokinetics

• Form/route: Commonly used intraperitoneal or subcutaneous in rodents; oral PK in mammals is poorly characterized.

• Exposure: Reported tissue penetration into adipose and liver; detailed human PK/PD unknown.

• Half-life/clearance: Not fully defined; likely rapid clearance via hepatic/renal routes typical of small cationic heteroaromatics.

• Medicinal chemistry: 5-Amino-1MQ is a tool compound; next-generation NNMT inhibitors with improved potency/selectivity/PK are in development.

4. Pre-clinical and Translational Evidence

4.1 Obesity & Insulin Resistance

In diet-induced-obese mice, 5-Amino-1MQ reduced weight and fat mass, improved insulin tolerance, and increased energy expenditure, with histology showing smaller adipocytes and reduced macrophage crown-like structures.

4.2 Hepatic Steatosis & Lipids

Rodent NAFLD models demonstrate lower hepatic triglycerides, reduced de novo lipogenesis, and improved plasma lipid profiles under NNMT inhibition.

4.3 NAD⁺/Epigenetic Coupling

Across adipose and stromal cells, NNMT blockade raises NAD⁺, activates sirtuins, and restores methylation capacity, reversing disease-associated transcriptional signatures.

4.4 Oncology (mechanistic)

NNMT overexpression is linked to poor prognosis and global hypomethylation in several cancers; 5-Amino-1MQ reduces migratory/EMT phenotypes in vitro and sensitizes some models to therapy—data remain pre-clinical.

Evidence quality note: Most efficacy and safety data are animal/cell-based. Human trials with 5-Amino-1MQ have not been published; effects should be considered hypothesis-generating.

5. Emerging Clinical Interests

6. Safety and Tolerability

• Human safety: No clinical safety datasets for 5-Amino-1MQ.

• Pre-clinical: Generally well-tolerated over short courses in rodents; systematic GLP tox not publicly available.

• Mechanism-based cautions:

  • Methylation biology: Sustained NNMT inhibition alters SAM utilization and epigenetic marks—long-term genomic/epigenomic safety is unknown.

  • NAD⁺ flux: Rapid NAD⁺ shifts can influence sirtuin and PARP activity; theoretical interactions with DNA-repair and redox.

  • 1-MNA signalling: Decreasing 1-MNA may remove vasculoprotective/anti-inflammatory signals reported for that metabolite in specific contexts.

Comparative safety matrix

7. Regulatory Landscape

• Status: 5-Amino-1MQ is not approved for human use; appears on research-chemical markets without quality control.

• Drug development: Multiple proprietary NNMT inhibitor series are in pre-clinical development; no approved NNMT-targeting drugs as of 2025.

• Use advisory: Any human use outside a trial is unsupported and may carry unknown risk.

8. Future Directions

• Medicinal chemistry: Improve potency, selectivity, and PK (oral bioavailability, brain/peripheral selectivity).

• Biomarkers: Develop pharmacodynamic markers (plasma/urine 1-MNA, tissue NAD⁺, SAM/SAH ratio, histone methylation).

• Indication mapping: Prioritize visceral-obesity/NAFLD phenotypes and NNMT-high tumours with molecular stratification.

• Combination therapy: Pair with lifestyle or GLP-1/GIP agents (metabolic) or epigenetic/IO drugs (oncology) for synergy.

• Safety program: Long-term studies on epigenome stability, fertility, and tumour promotion/suppression risk.

Selected References

• Cell Metabolism; iScience — NNMT inhibition reduces adiposity and increases energy expenditure in obese mice.

• Diabetes; Metabolism — Improvements in insulin sensitivity and glycaemic control with NNMT blockade.

• Nature Communications; The Journal of Biological Chemistry — NAD⁺ salvage coupling and sirtuin activation downstream of NNMT inhibition.

• Nature; Cell Reports — The “methylation sink” role of NNMT and reversal of epigenetic dysregulation.

• Hepatology; Liver International — Hepatic lipid metabolism and steatosis improvements in NNMT-targeted models.

• Science Advances; JCI Insight — Anti-fibrotic signatures after restoring SAM/SAH balance.

• Cancer Research; Nature Cell Biology — NNMT overexpression in cancer and metabolic-epigenetic rewiring; effects of inhibitors on migration/EMT.

• Cardiovascular Diabetology; Frontiers in Endocrinology — Adipose inflammation and cardiometabolic markers with NNMT inhibition.

• FASEB Journal; American Journal of Physiology–Endocrinology — Oxidative/thermogenic gene programs and VO₂ changes under NNMT blockade.