 acetate Chemical Structure.png)
IM156 (also known as HL-156A; Lixumistat; HL-271) is a metformin derivative thac acts as a novel and highly potent AMPK activator that increases AMPK phosphorylation. IM156 attenuates aging-associated cognitive impairment in animal model.
Physicochemical Properties
| Molecular Formula | C15H20F3N5O3 |
| Molecular Weight | 375.3462 |
| Exact Mass | 375.15 |
| Elemental Analysis | C, 48.00; H, 5.37; F, 15.18; N, 18.66; O, 12.79 |
| CAS # | 1422365-94-3 |
| Related CAS # | Lixumistat hydrochloride;1422365-52-3;Lixumistat;1422365-93-2; 2043654-98-2 (mesylate); 2043654-97-1; 1422365-52-3 (HCl); 2043654-70-0 (malonate); 2043654-72-2 (furmate); 1422365-94-3 (acetate); 2043654-64-2 (TFA) |
| PubChem CID | 154573779 |
| Appearance | White to off-white solid powder |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 26 |
| Complexity | 455 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | FC(OC1C([H])=C([H])C(=C([H])C=1[H])/N=C(\N([H])[H])/N=C(\N([H])[H])/N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H])(F)F.O([H])C(C([H])([H])[H])=O |
| InChi Key | AGFDCTOLSXWRDZ-UHFFFAOYSA-N |
| InChi Code | 1S/C13H16F3N5O.C2H4O2/c14-13(15,16)22-10-5-3-9(4-6-10)19-11(17)20-12(18)21-7-1-2-8-21;1-2(3)4/h3-6H,1-2,7-8H2,(H4,17,18,19,20);1H3,(H,3,4) |
| Chemical Name | N-(Imino((4-(trifluoromethoxy)phenyl)amino)methyl)-1-pyrrolidinecarboximidamide, acetate |
| Synonyms | IM156 acetate Lixumistat IM-156 IM 156 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | AMPK; OXPHOS/oxidative phosphorylation |
| ln Vitro | Lixumistat (acetate) (0.31-10 μM) phosphorylates AMPKα1 Thr172 in NIH3T3 murine fibroblasts in a way that is dependent on both time and dose [1]. Acetate, or lixumistat, has no effect on the expression of important glucose homeostasis-related factors such phosphoenolpyruvate carboxykinase 1 (Pck1) or glucose-6-phosphatase (G6pase) [1]. |
| ln Vivo | In mice with diet-induced obesity, lixumistat (acetate) had no effect on metabolic regulation as measured by body weight, blood glucose, insulin levels, and lipid metabolic content [1]. Lixumistat (acetate) (50 mg/kg; for 2 months) has no effect on anxiety, weight, or mobility in general [2]. The aging-related reduction in spatial working memory and new object recognition memory can be considerably mitigated by lixumistat (acetate) [2]. Aged mice's hippocampal AMPK activity is markedly elevated by lixumistat (acetate) [2]. |
| Enzyme Assay | Metformin is a treatment of choice for patients with type 2 diabetes. Its action involves the phosphorylation of 5'-adenosine monophosphate activated protein kinase (AMPK), leading to inhibition of liver gluconeogenesis. The effects of a novel chemical compound derived from metformin, HL271, on molecular and physiological actions involving AMPK and rhythmically-expressed circadian clock genes were investigated. HL271 potently activated AMPK in a dose-dependent manner, and produced shortening of the circadian period and enhanced degradation of the clock genes PER2 and CRY1. Although the molecular effects of HL271 resembled those of metformin, it produced different physiological effects in mice with diet-induced obesity. HL271 did not elicit glucose-lowering or insulin-sensitizing effects, possibly because of altered regulation of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1. This indicated that, although HL271 acted on circadian clock machinery through a similar molecular mechanism to metformin, it differed in its systemic effect on glucose and lipid metabolite regulations[1]. |
| Cell Assay |
Western Blot analysis [1] Cell Types: NIH3T3 cells Tested Concentrations: 0.31 μM, 0.62 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM Incubation Duration: 4 hrs (hours) Experimental Results: AMPK phosphorylation rate was Dramatically increased. |
| Animal Protocol |
Animal/Disease Models: C57BL/6J mice (young group/12-16 weeks, old group/20-22 months) [2] Doses: 50 mg/kg Route of Administration: Orally (drinking water), lasting 2 months Experimental Results: Attenuates age-related cognitive decline. Animal care and experimental procedures followed the guidelines of the Institutional Animal Care and Use Committee of the Institute of Basic Science (IBS). Experiments were performed with male and female C57BL/6J mice (12~16 weeks of age for the young group and 20~22 months of age for the old groups). Group-housed mice were separated into single cages for acclimatization one month before beginning drug treatment. Mice were housed under controlled temperature and light conditions (23℃, 12-h light:12-h dark cycle). Experiments were performed during the light phase. The old mice were divided into three groups and orally treated with normal drinking water (control), metformin solution (100 mg/kg), or HL271 solution (50 mg/kg) for 2 months.[2] |
| References |
[1]. HL271, a novel chemical compound derived from metformin, differs from metformin in its effects on the circadian clock and metabolism. Biochem Biophys Res Commun. 2016 Jan 15;469(3):783-9. [2]. The Improving Effect of HL271, a Chemical Derivative of Metformin, a Popular Drug for Type II Diabetes Mellitus, on Aging-induced Cognitive Decline. Exp Neurobiol. 2018 Feb;27(1):45-56. [3]. Phase I study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors. Journal of Clinical Oncology 38(15_suppl):3590-3590. |
| Additional Infomation | Lixumistat Acetate is the acetate salt form of lixumistat, an orally bioavailable biguanide compound and mitochondrial oxidative phosphorylation (OxPhos) inhibitor, with potential antineoplastic activity. Upon administration, lixumistat inhibits oxidative phosphorylation, decreases mitochondrial function, prevents tumor cell metabolism and deprives tumor cells of energy, thereby preventing tumor cell proliferation. Mitochondrial OxPhos is overactivated in cancer cells and plays a key role in tumor cell proliferation. Drug resistant tumor cells are very susceptible to decreased mitochondrial OxPhos as they cannot easily compensate for the decrease in mitochondrial function by increasing glycolysis. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~266.42 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.66 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.66 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (6.66 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6642 mL | 13.3209 mL | 26.6418 mL | |
| 5 mM | 0.5328 mL | 2.6642 mL | 5.3284 mL | |
| 10 mM | 0.2664 mL | 1.3321 mL | 2.6642 mL |