AK-7Selective SIRT2 inhibitor; brain penetrant CAS# 420831-40-9 |
- AVL-292 benzenesulfonate
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| Cas No. | 420831-40-9 | SDF | Download SDF |
| PubChem ID | 1328033 | Appearance | Powder |
| Formula | C19H21BrN2O3S | M.Wt | 437.35 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 50 mg/mL (114.32 mM) H2O : < 0.1 mg/mL (insoluble) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 3-(azepan-1-ylsulfonyl)-N-(3-bromophenyl)benzamide | ||
| SMILES | C1CCCN(CC1)S(=O)(=O)C2=CC=CC(=C2)C(=O)NC3=CC(=CC=C3)Br | ||
| Standard InChIKey | IYAYHZZWYNXHEQ-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C19H21BrN2O3S/c20-16-8-6-9-17(14-16)21-19(23)15-7-5-10-18(13-15)26(24,25)22-11-3-1-2-4-12-22/h5-10,13-14H,1-4,11-12H2,(H,21,23) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Selective SIRT2 inhibitor (IC50 = 15.5 μM); displays no effect on SIRT1 or SIRT3. Decreases neuronal cholesterol levels; improves motor function and ameliorates brain atrophy in a mouse model of Huntington's disease. Brain penetrant. |
AK-7 Dilution Calculator
AK-7 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.2865 mL | 11.4325 mL | 22.865 mL | 45.73 mL | 57.1625 mL |
| 5 mM | 0.4573 mL | 2.2865 mL | 4.573 mL | 9.146 mL | 11.4325 mL |
| 10 mM | 0.2286 mL | 1.1432 mL | 2.2865 mL | 4.573 mL | 5.7162 mL |
| 50 mM | 0.0457 mL | 0.2286 mL | 0.4573 mL | 0.9146 mL | 1.1432 mL |
| 100 mM | 0.0229 mL | 0.1143 mL | 0.2286 mL | 0.4573 mL | 0.5716 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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AK-7 is a selective cell- and brain-permeable SIRT2 inhibitor, with an IC50 of 15.5 μM.
In Vitro:AK-7 (10 μM) reduces cholesterol levels in naive N2a neuroblastoma cells and hippocampal slice cultures from wild-type mice. AK-7 (1 μM) shows neuroprotective effect of AK-7 in striatal Huntington’s disease (HD) neurons[1]. AK-7 (12.5 μM) decreases ratio of DA neurons in primary midbrain cultures[3].
In Vivo:AK-7 (15 mg/kg/dose, i.p.) is brain-permeable in wild-type and HD mice[1]. AK-7 (10, 20 mg/kg, i.p.) improves the behavior and neuropathological phenotype and extends survival of R6/2 HD mice. AK-7 (20 mg/kg) ameliorates HD neuropathology in R6/2 mice. AK-7 also reduces the polyglutamine aggregation in R6/2 brain. In addition, AK-7 treated 140CAG mice show motor performance changes that parallel untreated wild-type mice, with the 20 mg/kg dose being most effective and significantly different from untreated 140CAG mice[2].
References:
[1]. Taylor DM, et al. A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of sirtuin 2 deacetylase. ACS Chem Biol. 2011 Jun 17;6(6):540-6.
[2]. Chopra V, et al. The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington's disease mouse models. Cell Rep. 2012 Dec 27;2(6):1492-7.
[3]. Szego EM, et al. Sirtuin 2 enhances dopaminergic differentiation via the AKT/GSK-3β/β-catenin pathway. Neurobiol Aging. 2017 Aug;56:7-16.
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The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington's disease mouse models.[Pubmed:23200855]
Cell Rep. 2012 Dec 27;2(6):1492-7.
Inhibition of sirtuin 2 (SIRT2) deacetylase mediates protective effects in cell and invertebrate models of Parkinson's disease and Huntington's disease (HD). Here we report the in vivo efficacy of a brain-permeable SIRT2 inhibitor in two genetic mouse models of HD. Compound treatment resulted in improved motor function, extended survival, and reduced brain atrophy and is associated with marked reduction of aggregated mutant huntingtin, a hallmark of HD pathology. Our results provide preclinical validation of SIRT2 inhibition as a potential therapeutic target for HD and support the further development of SIRT2 inhibitors for testing in humans.
Aging-related 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurochemial and behavioral deficits and redox dysfunction: improvement by AK-7.[Pubmed:27235848]
Exp Gerontol. 2016 Sep;82:19-29.
Aging is a prominent risk factor for the occurrence and progression of Parkinson disease (PD). Aging animals are more significant for PD research than young ones. It is promising to develop effective treatments for PD through modulation of aging-related molecules. Sirtuin 2 (SIRT2), a strong deacetylase highly expressed in the brain, has been implicated in the aging process. In our present study, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 12mg/kg once daily) was observed to bring about significant behavioral deficits and striatal dopamine depletion in aging male and female mice, while it did not do so in young animals. MPTP did not cause significant reduction in striatal 5-hydroxytryptamine content in aging male and female mice. Furthermore, we observed that MPTP treatment resulted in significant reduction in GSH content and significant increase in MDA content and SIRT2 expression in the substantia nigra (SN) of aging mice, while it did not do so in young animals. Importantly, we observed that AK-7 (a selective SIRT2 inhibitor) significantly improved behavior abnormality and neurochemical deficits in aging male and female mice treated with MPTP. Significant increase in GSH content and significant decrease in MDA content were also observed in the SN of aging male and female mice co-treated with MPTP and AK-7 compared with the MPTP-treated animals. Our results indicated that MPTP induce aging-related neurochemical and behavioural deficits and dysfunction of redox network in male and female mice and AK-7 may be neuroprotective in PD through modulating redox network.
Aging-related rotenone-induced neurochemical and behavioral deficits: role of SIRT2 and redox imbalance, and neuroprotection by AK-7.[Pubmed:26089639]
Drug Des Devel Ther. 2015 May 7;9:2553-63.
Aging is one of the strongest risk factors for Parkinson's disease (PD). SIRT2 has been implicated in the aging process. It is pertinent to investigate the role of SIRT2 in aging-related dopaminergic neurotoxicity and to develop effective therapeutic strategies for PD through the use of aging animals. In this study, we observed that rotenone induced significant behavior abnormality and striatal dopamine depletion in aging rats, while it did not do so in young rats. No significant change in striatal serotonin level was observed in the aging rats after rotenone administration. There was also aging-related rotenone-induced increase in substantia nigra (SN) SIRT2 expression in the rats. In addition, there was aging-related rotenone-induced SN malondialdehyde (MDA) increase and glutathione (GSH) decrease in the rats. No significant changes in cerebellar SIRT2, MDA, or GSH levels were observed in the aging rats after rotenone administration. Striatal dopamine content was significantly inversely correlated with SN SIRT2 expression in the rats. AK-7 significantly diminished striatal dopamine depletion and improved behavior abnormality in the rotenone-treated aging rats. Furthermore, AK-7 significantly decreased MDA content and increased GSH content in the SN of rotenone-treated aging rats. Finally, the effect of AK-7 on dopaminergic neurons and redox imbalance was supported by the results from primary mesencephalic cultures. Our study helps to elucidate the mechanism for the participation of aging in PD and suggests that SN SIRT2 may be involved in PD neurodegeneration, that AK-7 may be neuroprotective in PD, and that maintaining redox balance may be one of the mechanisms underlying neuroprotection by AK-7.
A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of sirtuin 2 deacetylase.[Pubmed:21370928]
ACS Chem Biol. 2011 Jun 17;6(6):540-6.
Sirtuin 2 (SIRT2) deacetylase-dependent inhibition mediates neuroprotective reduction of cholesterol biosynthesis in an in vitro Huntington's disease model. This study sought to identify the first brain-permeable SIRT2 inhibitor and to characterize its cholesterol-reducing properties in neuronal models. Using biochemical sirtuin deacetylation assays, we screened a brain-permeable in silico compound library, yielding 3-(1-azepanylsulfonyl)-N-(3-bromphenyl)benzamide as the most potent and selective SIRT2 inhibitor. Pharmacokinetic studies demonstrated brain-permeability but limited metabolic stability of the selected candidate. In accordance with previous observations, this SIRT2 inhibitor stimulated cytoplasmic retention of sterol regulatory element binding protein-2 and subsequent transcriptional downregulation of cholesterol biosynthesis genes, resulting in reduced total cholesterol in primary striatal neurons. Furthermore, the identified inhibitor reduced cholesterol in cultured naive neuronal cells and brain slices from wild-type mice. The outcome of this study provides a clear opportunity for lead optimization and drug development, targeting metabolic dysfunctions in CNS disorders where abnormal cholesterol homeostasis is implicated.
