Research Brief
5-Amino-1MQ: Safety Profile & Research Summary
Preclinical Animal Studies
⚠️ Important: There are no completed or published human clinical trials for 5-Amino 1MQ. All efficacy data below is from preclinical (cell culture and animal) studies only.
- Obesity — DIO Mice (Neelakantan 2018): 20 mg/kg SC 3×/day, 11 days. -5.1% body weight (P<0.0001 at day 10), -35% WAT mass (P<0.001), >30% decreased adipocyte size and >40% decreased volume (P<0.05), ~30% lower plasma cholesterol (P<0.05). No change in food intake; no adverse toxicity. [2]
- Obesity + Diet (Sampson 2021): 32 mg/kg SC daily, ~7 weeks (DIO mice switched to lean diet). -29.3% fat mass from baseline vs. -2.9% for diet alone. Body composition normalized to lean controls. Metabolomic analysis predicted lipid synthesis inhibition (z-score = -2.566, P=0.045). [9]
- Microbiome (Dimet-Wiley 2022): 32 mg/kg SC daily, ~7 weeks. Treated mice showed distinct microbiome cluster with increased Lactobacillus and Parasutterella; decreased Erysipelatoclostridium. [15]
- Metabolic/Liver (Babula 2024): Daily SC, 28 days (DIO mice). Normalized ALT/AST, improved oral glucose tolerance, suppressed hyperinsulinemia, reduced liver weight and triglycerides, attenuated steatosis and macrophage infiltration. [12]
- Exercise Mimicry (Dimet-Wiley 2024): 10 mg/kg SC daily, 8 weeks (aged 22-month mice). Sedentary treated: +40% grip strength (P<0.001). Exercise + treated: +60% grip strength, maintained 1.8 km/day running increase at week 8 (P=0.0039). >30% reduction in intramyocellular lipid. [10]
- Muscle Regeneration (Neelakantan 2019): 5–10 mg/kg, 1–3 weeks (aged 24-month mice with acute injury). ~2× myofiber CSA, +70% peak torque (P<0.05), increased MuSC proliferation and fusion. [11]
- Peripheral Artery Disease (Dong 2025): Daily dosing (BALB/cJ mice with hindlimb ischemia). Significantly improved muscle strength (P<0.0001), power (P=0.031), total work (P=0.037). Independent of perfusion or capillary changes. [16]
Pharmacokinetic Profile (Rats)
Awosemo/Neelakantan et al. (2021): Oral bioavailability 38.4%; T½ 6.9h (oral) / 3.8h (IV); Cmax 2,252 ng/mL. High membrane permeability. No 24-hour accumulation in heart, liver, kidney, or brain (recirculation noted at ~12h). Cross-species liver metabolic stability confirmed. [7]
reported tolerability profile (Preclinical)
Acute Toxicity: In mice, animals survived doses from 50 mg/kg to 2,000–5,000 mg/kg with no observable adverse reactions during 48-hour monitoring. [2]
Subacute Toxicity (14 days): Liver (AST, GGT), heart (troponin I), and inflammatory (CRP) markers were unaffected except for significant CRP rise at highest IV dose (200 mg/kg) at 6 hours post-dose. [2]
Cell Viability: No impact up to 100 µM; modest cytotoxicity at 100–300 µM; ~40% cytotoxicity at 600 µM in 3T3-L1 adipocytes. [1]
Clinical Development Status
Ridgeline Therapeutics (founded by Dr. Watowich) is developing a lead NNMT inhibitor candidate (RT-002), conducting IND-enabling GLP toxicology studies in minipigs with the goal of submitting an IND briefing package to the FDA for Phase 1 first-in-human clinical trials. [6]
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References
- Neelakantan H, Wang HY, Vance V, et al. Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase. J Med Chem, 60(12), 5015–5028, 2017.
- Neelakantan H, Brightwell CR, Graber TG, et al. Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice. Biochem Pharmacol, 147, 141–152, 2018.
- Neelakantan H, Vance V, Wetzel MD, et al. Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase. J Med Chem, 60(12), 5015-5028, 2017.
- Sun WD, Zhu GY, Li J, et al. Nicotinamide N-methyltransferase (NNMT): a novel experimental target for metabolic syndrome. Front Pharmacol, 15, 1410479, 2024.
- World Anti-Doping Agency (WADA). The World Anti-Doping Code International Standard: Prohibited List 2025. S0: Non-Approved Substances.
- Watowich SJ. SBIR Award: NNMT Inhibitor Development. National Institute on Aging (NIA), 2021.
- Awosemo O, Neelakantan H, Watowich SJ, et al. Development & Validation of LC–MS/MS Assay for 5-Amino-1-Methyl Quinolinium in Rat Plasma. J Pharm Biomed Anal, 204, 114255, 2021.
- Liu JR, Deng ZH, Zhu XJ, et al. Roles of Nicotinamide N-Methyltransferase in Obesity and Type 2 Diabetes. BioMed Res Int, 2021, 9924314, 2021.
- Sampson CM, Dimet AL, Neelakantan H, et al. Combined nicotinamide N-methyltransferase inhibition and reduced-calorie diet normalizes body composition in obese mice. Sci Rep, 11(1), 5637, 2021.
- Dimet-Wiley AL, Latham CM, Brightwell CR, et al. Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice. Sci Rep, 14(1), 15554, 2024.
- Neelakantan H, Vance V, Wang HYL, et al. Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle. Biochem Pharmacol, 163, 481–492, 2019.
- Babula J, Dimet-Wiley AL, Seyoum B, et al. Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction. Diabetes Obes Metab, 26(11), 5272–5282, 2024.
- Li XY, Pi YN, Chen Y, et al. Nicotinamide N-Methyltransferase: A Promising Biomarker and Target for Human Cancer Therapy. Front Oncol, 12, 894744, 2022.
- Moody TW, Nuche-Berenguer B, Jensen RT. Cancer and NNMT overexpression in aggressive tumors. Curr Opin Endocrinol Diabetes Obes, 2022.
- Dimet-Wiley A, Sampson CM, Neelakantan H, et al. Reduced calorie diet combined with NNMT inhibition establishes a distinct microbiome in DIO mice. Sci Rep, 12(1), 484, 2022.
- Dong G, Latham CM, Brightwell CR, et al. Nicotinamide N-methyltransferase inhibition improves limb function in experimental peripheral artery disease. Acta Physiol, 2025.
- Watowich S, Neelakantan H, McHardy SF. Quinoline derived small molecule inhibitors of nicotinamide N-methyltransferase (NNMT) and uses thereof. U.S. Patent No. 12,071,409, August 27, 2024.
- Watowich S, Neelakantan H, McHardy SF. Quinoline derived small molecule inhibitors of nicotinamide N-methyltransferase (NNMT) and uses thereof. U.S. Patent No. 11,401,243, August 2, 2022.
Related Research Questions
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