KML 29
目录号 : GC17385
An inhibitor of MAGL
Cas No.:1380424-42-9
Sample solution is provided at 25 µL, 10mM.
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KML 29 is reported to display IC50 values of 43, 15, and 5.9 nM toward rat, mouse, and human monoacylglycerol lipase (MAGL), respectively [1]. KML29 potently and selectively inhibited MAGL in vitro and in vivo with minimal cross-reactivity toward other central and peripheral serine hydrolases, including no detectable activity against FAAH [1].
KML 29 acted as a selective MAGL inhibitor showed antiproliferative activity against B16-F10 and HT-29 cells, while showed no significant effect on A431, H1975, OVCAR-3, HCC827, Hela and A549 cell lines [2].
KML 29 delays onset, progression and survival in the low-copy SOD1G93A Amyotrophic lateral sclerosis (ALS) mouse. oral administration of KML 29 is therapeutic by delaying onset, improving symptoms and extending lifespan, which was associated with increasing tissue levels of neurotrophic factors and decreasing pro-inflammatory cytokines [3]. Acute administration of KML 29 mostly increased 2-AG levels in fat, brain and spinal cord without any effect on AEA levels. KML 29 also reduced arachidonic acid levels in the CNS and peripheral organs [4].
References:
[1]. J.W. Chang, M.J. Niphakis, K.M. Lum, A.B. Cognetta 3rd, C. Wang, M.L. Matthews, S. Niessen, M.W. Buczynski, L.H. Parsons, B.F. Cravatt. Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates. Chem. Biol., 19 (2012), pp. 579-588
[2]. Deng H, Lei Q, Yang N, et al. Discover Monoacylglycerol Lipase Inhibitors by Combination of Fluorogenic Substrate Assay and Activity-Based Protein Profiling[J]. Frontiers in pharmacology, 2022: 3328.
[3]. N. Pasquarelli, M. Engelskirchen, J. Hanselmann, S. Endres, C. Porazik, H. Bayer, E. Buck, M. Karsak, P. Weydt, B. Ferger, A. Witting. Evaluation of monoacylglycerol lipase as a therapeutic target in a transgenic mouse model of ALS. Neuropharmacology, 124 (2017), pp. 157-169
[4]. N Pasquarelli, et al., Comparative biochemical characterization of the monoacylglycerol lipase inhibitor KML29 in brain, spinal cord, liver, spleen, fat and muscle tissue. Neuropharmacology 91, 148-156 (2015).
据报道，KML 29 对大鼠、小鼠和人单酰基甘油脂肪酶 (MAGL) 的 IC50 值分别为 43、15 和 5.9 nM [1]。 KML29 在体外和体内有效且选择性地抑制 MAGL，对其他中枢和外周丝氨酸水解酶的交叉反应最小，包括对 FAAH [1] 的可检测活性。
作为选择性 MAGL 抑制剂的 KML 29 对 B16-F10 和 HT-29 细胞显示出抗增殖活性，而对 A431、H1975、OVCAR-3、HCC827、Hela 和 A549 细胞系没有显着影响[2 ].
KML 29 延迟低拷贝 SOD1G93A 肌萎缩侧索硬化 (ALS) 小鼠的发病、进展和存活。口服 KML 29 具有延缓发作、改善症状和延长寿命的治疗作用，这与组织中神经营养因子水平的升高和促炎细胞因子的降低有关[3]。 KML 29 的急性给药主要增加脂肪、脑和脊髓中的 2-AG 水平，而对 AEA 水平没有任何影响。 KML 29 还降低了中枢神经系统和外周器官中的花生四烯酸水平[4]。
| Cell experiment [1]: | |
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Cell lines |
A431, H1975, B16-F10, OVCAR-3, HT-29, HCC827, Hela, A549 |
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Preparation Method |
cells (~1,000 per well) in 100 µl of culture medium were plated in a 96-well plate for 24 h and 100 µl of medium with KML29 was added to each well for 48 h. Then 10 µl of CCK8 solution was added and incubated at 37℃ for 2 h. |
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Reaction Conditions |
20 µM KML29 for 48 h |
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Applications |
The selective MAGL inhibitor KML29 showed antiproliferative activity against B16-F10 and HT-29 cells. |
| Animal experiment [2]: | |
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Animal models |
MCAO rats |
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Preparation Method |
1 mg/kg KML 29, a potent covalent inhibitor of MAGL, was administered intravenously for three days. |
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Dosage form |
intravenous injection, 1 mg/kg/d for 3 days |
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Applications |
Treatment with KML 29 reduced the area showing lower radioactivity in the ipsilateral region. In the ipsilateral side of the ischemia rat with no medication, the AUC ratios in the cortex and striatum were 0.49 ± 0.04 and 0.73 ± 0.02, respectively. The corresponding ratios were improved 0.72 ± 0.07 in the cortex and 0.88 ± 0.04 in the striatum by KML 29 treatment, respectively. |
|
References: [1]: Deng H, Lei Q, Yang N, et al. Discover Monoacylglycerol Lipase Inhibitors by Combination of Fluorogenic Substrate Assay and Activity-Based Protein Profiling[J]. Frontiers in pharmacology, 2022: 3328. |
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| Cas No. | 1380424-42-9 | SDF | |
| 化学名 | 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(benzo[d][1,3]dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate | ||
| Canonical SMILES | FC(F)(F)C(OC(N1CCC(C(C2=CC3=C(OCO3)C=C2)(O)C4=CC5=C(OCO5)C=C4)CC1)=O)C(F)(F)F | ||
| 分子式 | C24H21F6NO7 | 分子量 | 549.42 |
| 溶解度 | DMSO: 2 mg/ml | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.8201 mL | 9.1005 mL | 18.201 mL |
| 5 mM | 0.364 mL | 1.8201 mL | 3.6402 mL |
| 10 mM | 0.182 mL | 0.9101 mL | 1.8201 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet