TES-991
目录号 : GC31342
TES-991是一种有效的、有选择性的人α-氨基-β-羧基粘康酸-ε-半醛脱羧酶(ACMSD)抑制剂，IC50为3nM。
Cas No.:1883602-20-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
TES-991 is a potent and selective human α?Amino-β-carboxymuconate-ε-semialdehyde Decarboxylase (ACMSD) inhibitor, with an IC50 of 3 nM.
TES-991 (compounds 21) is able to significantly increase intracellular NAD+ levels, providing further proof of their mechanism of action. TES-991 shows an inhibition of cytochrome P450 2C19, suggesting a possible involvement of the 2H-tetrazole motif in this interaction[1].
After the intravenous administration of 0.5 mg/kg, TES-991 (compound 21) shows low blood clearance, with low volumes of distribution and halflives (t1/2) of about 4.0 and 5.0 h, respectively, although after oral administration at 5 mg/kg, the blood concentrations of TES-991 is quantifiable for up to 8 h. A moderate systemic exposure is observed for the 2H-tetrazole analogue, TES-991, a good systemic exposure is recorded for the free acid[1].
[1]. Pellicciari R, et al. α-Amino-β-carboxymuconate-ε-semialdehyde Decarboxylase (ACMSD) Inhibitors as Novel Modulators of De Novo Nicotinamide Adenine Dinucleotide (NAD+) Biosynthesis. J Med Chem. 2018 Feb 8;61(3):745-759.
| Cas No. | 1883602-20-7 | SDF | |
| Canonical SMILES | N#CC1=C(C2=CC=CS2)NC(SCC3=CC=CC(C4=NN=NN4)=C3)=NC1=O | ||
| 分子式 | C17H11N7OS2 | 分子量 | 393.45 |
| 溶解度 | DMSO : 62.5 mg/mL (158.85 mM);Water : < 0.1 mg/mL (insoluble) | 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 | 2.5416 mL | 12.7081 mL | 25.4162 mL |
| 5 mM | 0.5083 mL | 2.5416 mL | 5.0832 mL |
| 10 mM | 0.2542 mL | 1.2708 mL | 2.5416 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。
De novo NAD+ synthesis enhances mitochondrial function and improves health
Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here we show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-β-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. We also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, we identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.
Itaconate alleviates β2-microglobulin-induced cognitive impairment by enhancing the hippocampal amino-β-carboxymuconate-semialdehyde-decarboxylase/picolinic acid pathway
β2-microglobulin (B2M) has been established to impair cognitive function. However, no treatment is currently available for B2M-induced cognitive dysfunction. Itaconate is a tricarboxylic acid (TCA) cycle intermediate that exerts neuroprotective effects in several neurological diseases. The amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD)/picolinic acid (PIC) pathway is a crucial neuroprotective branch in the kynurenine pathway (KP). The present study sought to investigate whether Itaconate attenuates B2M-induced cognitive impairment and examine the mediatory role of the hippocampal ACMSD/PIC pathway. We demonstrated that 4-Octyl Itaconate (OI, an itaconate derivative) significantly alleviated B2M-induced cognitive dysfunction and hippocampal neurogenesis impairment. OI treatment also increased the expression of ACMSD, elevated the concentration of PIC, and decreased the level of 3-HAA in the hippocampus of B2M-exposed rats. Furthermore, inhibition of ACMSD by TES-991 significantly abolished the protections of Itaconate against B2M-induced cognitive impairment and neurogenesis deficits. Exogenous PIC supplementation in hippocampus also improved cognitive performance and hippocampal neurogenesis in B2M-exposed rats. These findings demonstrated that Itaconate alleviates B2M-induced cognitive impairment by upregulation of the hippocampal ACMSD/PIC pathway. This is the first study to document Itaconate as a promising therapeutic agent to ameliorate cognitive impairment. Moreover, the mechanistic insights into the ACMSD/PIC pathway improve our understanding of it as a potential therapeutic target for neurological diseases beyond B2M-associated neurocognitive disorders.