3-氨基-6-[4-(4-甲基哌嗪-1-基)磺酰基苯基]-n-吡啶-3-基吡嗪-2-羧酰胺 | 486424-20-8

• 物质功能分类: 生物化工 - 抑制剂 - PI3K/Akt/mTOR抑制剂(PI3K/Akt/mTOR)
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 3-氨基-6-[4-(4-甲基哌嗪-1-基)磺酰基苯基]-n-吡啶-3-基吡嗪-2-羧酰胺
• 英文名称: AZD2858
• 英文别名: 3-amino-6-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]-N-pyridin-3-ylpyrazine-2-carboxamide；3-Amino-6-{4-[(4-Methylpiperazin-1-Yl)sulfonyl]phenyl}-N-Pyridin-3-Ylpyrazine-2-Carboxamide
• CAS: 486424-20-8
• 化学式: C₂₁H₂₃N₇O₃S
• 分子量: 453.525
• InChiKey: FHCSBLWRGCOVPT-UHFFFAOYSA-N

物化性质

• 密度：
  1.408±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO:8.0(最大浓度 mg/mL);17.64(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  143
• 氢给体数：
  2
• 氢受体数：
  9

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

AZD2858一种选择性的GSK-3抑制剂，IC50为68 nM，激活Wnt信号通路，增强大鼠的骨质。

体外研究

AZD2858是选择性的GSK-3抑制剂，IC50 是68 nM，抑制tau 396位点的磷酸化，激活Wnt信号通路。AZD2858 处理(1 μM, 12 h)分离的人成骨细胞导致β-catenin水平增加3倍。在人和大鼠的间充质干细胞中，AZD2858引起β-catenin稳定，激活体外成骨细胞和成骨细胞钙化的hADSC定型。

体内研究

与对照组相比，大鼠口服AZD2858治疗两周后引起骨密度剂量依赖增加，治疗两周后，在每天20 毫克/千克(总BMC: 对照组的172%)剂量下具有最大疗效。在皮层中也会发现小而显著的效果(总BMC: 对照组的111%)。AZD2858处理大鼠(30 微摩尔/千克)三周后出现胼胝中矿物质密度(2周时28% ，三周时38%)和矿物质含量(两周时81% ，三周时93%)增加。AZD2858处理使骨折恢复更快，有骨性骨痂但没有明显的软骨成分。 大鼠用AZD2858处理28天后，使血清中骨更新标志物和骨密度增加产生时间依赖性变化。大鼠用AZD2858处理7天后，骨形成标志P1NP增加，溶蚀标志物TRAcP-5b降低，这表明骨合成代谢增加，溶蚀作用减弱。

生物活性

AZD2858一种选择性的GSK-3抑制剂，IC50为68 nM，激活Wnt信号通路，增强大鼠的骨质。

靶点

Target	Value
GSK-3	68 nM

体外研究

AZD2858是选择性的GSK-3抑制剂，IC50 是68 nM，抑制tau 396位点的磷酸化，激活Wnt信号通路。AZD2858 处理(1 μM, 12 h)分离的人成骨细胞导致β-catenin水平增加3倍。在人和大鼠的间充质干细胞中，AZD2858引起β-catenin稳定，激活体外成骨细胞和成骨细胞钙化的hADSC定型。

体内研究

与对照组相比，大鼠口服AZD2858治疗两周后引起骨密度剂量依赖增加，治疗两周后，在每天20 毫克/千克(总BMC: 对照组的172%)剂量下具有最大疗效。在皮层中也会发现小而显著的效果(总BMC: 对照组的111%)。AZD2858处理大鼠(30 微摩尔/千克)三周后出现胼胝中矿物质密度(2周时28% ，三周时38%)和矿物质含量(两周时81% ，三周时93%)增加。AZD2858处理使骨折恢复更快，有骨性骨痂但没有明显的软骨成分。 大鼠用AZD2858处理28天后，使血清中骨更新标志物和骨密度增加产生时间依赖性变化。大鼠用AZD2858处理7天后，骨形成标志P1NP增加，溶蚀标志物TRAcP-5b降低，这表明骨合成代谢增加，溶蚀作用减弱。

反应信息

• 作为反应物：
  描述：

  3-氨基-6-[4-(4-甲基哌嗪-1-基)磺酰基苯基]-n-吡啶-3-基吡嗪-2-羧酰胺 在 盐酸 作用下， 以 甲醇 、 乙醚 、 二氯甲烷 为溶剂， 生成 3-amino-6-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-N-pyridin-3-ylpyrazine-2-carboxamide hydrochloride
  参考文献：
  名称：

  Discovery of Novel Potent and Highly Selective Glycogen Synthase Kinase-3β (GSK3β) Inhibitors for Alzheimer’s Disease: Design, Synthesis, and Characterization of Pyrazines

  摘要：

  Glycogen synthase kinase-3 beta, also called tau phosphorylating kinase, is a proline-directed serine/threonine kinase which was originally identified due to its role in glycogen metabolism. Active forms of GSK3 beta localize to pretangle pathology including dystrophic neuritis and neurofibrillary tangles in Alzheimer's disease (AD) brain. By using a high throughput screening (HTS) approach to search for new chemical series and cocrystallization of key analogues to guide the optimization and synthesis of our pyrazine series, we have developed highly potent and selective inhibitors showing cellular efficacy and blood-brain barrier penetrance. The inhibitors are suitable for in vivo efficacy testing and may serve as a new treatment strategy for Alzheimer's disease.

  DOI：

  10.1021/jm201724m
• 作为产物：
  描述：

  1-(4-溴苯基磺酰基)-4-甲基哌嗪 在 正丁基锂 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 水 、 silica gel 、 sodium carbonate 作用下， 以 四氢呋喃 、 乙醇 、 水 、 甲苯 为溶剂， 反应 18.5h， 生成 3-氨基-6-[4-(4-甲基哌嗪-1-基)磺酰基苯基]-n-吡啶-3-基吡嗪-2-羧酰胺
  参考文献：
  名称：

  Discovery of Novel Potent and Highly Selective Glycogen Synthase Kinase-3β (GSK3β) Inhibitors for Alzheimer’s Disease: Design, Synthesis, and Characterization of Pyrazines

  摘要：

  Glycogen synthase kinase-3 beta, also called tau phosphorylating kinase, is a proline-directed serine/threonine kinase which was originally identified due to its role in glycogen metabolism. Active forms of GSK3 beta localize to pretangle pathology including dystrophic neuritis and neurofibrillary tangles in Alzheimer's disease (AD) brain. By using a high throughput screening (HTS) approach to search for new chemical series and cocrystallization of key analogues to guide the optimization and synthesis of our pyrazine series, we have developed highly potent and selective inhibitors showing cellular efficacy and blood-brain barrier penetrance. The inhibitors are suitable for in vivo efficacy testing and may serve as a new treatment strategy for Alzheimer's disease.

  DOI：

  10.1021/jm201724m

文献信息

• Arylamines for the treatment of conditions associated with gsk-3
  申请人：Berg Stefan

  公开号：US20060052396A1

  公开（公告）日：2006-03-09

  The present invention relates to new compounds of formula (I) wherein Z, Y, X, P, Q, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , A, m and n are defined as in any one of claims 1 to 3, a process for their preparation and new intermediates prepared therein, pharmaceutical formulations containing said therapeutically active compounds and to the use of said active compounds for the treatment of conditions associated with glycogens synthase kinase-3 (GSK3).

  本发明涉及具有公式（I）的新化合物，其中Z、Y、X、P、Q、R、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、A、m和n的定义如权利要求1至3中的任意一项，以及制备它们的过程和其中制备的新中间体，含有所述治疗活性化合物的制药配方以及使用所述活性化合物治疗与糖原合酶激酶-3（GSK3）相关的疾病的方法。
• METHOD FOR PRODUCING SOMATIC CELL, SOMATIC CELL, AND COMPOSITION
  申请人：Kyoto Prefectural Public University Corporation

  公开号：EP3521419A1

  公开（公告）日：2019-08-07

  The present invention addresses the problem of providing: a method for producing brown adipocytes, osteoblasts, cartilage cells, neural cells or cardiac cells from somatic cells without performing artificial gene transfer; brown adipocytes, osteoblasts, cartilage cells, neural cells, or cardiac cells; or a composition including a combination of chemical substances that can be used for the aforementioned production method. An example of the present invention is a method for producing brown adipocytes, osteoblasts, cartilage cells, neural cells, or cardiac cells including a step for culturing somatic cells in the presence or absence of an inhibitor or activator selected from the group consisting of an ALK5 inhibitor, an ALK6 inhibitor, an AMPK inhibitor, a cAMP activator, an ALK2 inhibitor, an ALK3 inhibitor, a GSK3 inhibitor, and an Erk inhitibor.

  本发明所要解决的问题是提供：一种在不进行人工基因转移的情况下从体细胞生产棕色脂肪细胞、成骨细胞、软骨细胞、神经细胞或心脏细胞的方法；棕色脂肪细胞、成骨细胞、软骨细胞、神经细胞或心脏细胞；或一种可用于上述生产方法的包括化学物质组合的组合物。本发明的一个例子是一种生产棕色脂肪细胞、成骨细胞、软骨细胞、神经细胞或心脏细胞的方法，包括在有或没有选自下列组的抑制剂或激活剂的情况下培养体细胞的步骤：ALK5抑制剂、ALK6抑制剂、AMPK抑制剂、cAMP激活剂、ALK2抑制剂、ALK3抑制剂、GSK3抑制剂和Erk抑制剂。
• METHOD FOR PRODUCING INSULIN-PRODUCING CELLS
  申请人：Kataoka Corporation

  公开号：EP3747994A1

  公开（公告）日：2020-12-09

  The present invention chiefly aims to provide a process for directly inducing insulin-producing cells from somatic cells without performing artificial gene transfer. The present invention can include a process for producing an insulin-producing cell by inducing differentiation directly from a somatic cell, the process comprising a step of culturing the somatic cell in the presence of a cAMP inducer, and six members selected from the group consisting of a GSK3 inhibitor, a TGF-β inhibitor, a BMP inhibitor, a p53 inhibitor, a PI3K inhibitor, a Notch inhibitor and a RAR agonist, or all members thereof. The insulin-producing cells obtained by the present invention are useful in regenerative medicine and the like.

  本发明的主要目的是提供一种在不进行人工基因转移的情况下直接从体细胞诱导胰岛素产生细胞的工艺。本发明可包括通过直接从体细胞诱导分化产生胰岛素产生细胞的工艺，该工艺包括在cAMP诱导剂存在下培养体细胞的步骤，以及选自GSK3抑制剂、TGF-β抑制剂、BMP抑制剂、p53抑制剂、PI3K抑制剂、Notch抑制剂和RAR激动剂或其所有成员组成的组中的六个成员。本发明获得的胰岛素分泌细胞可用于再生医学等领域。
• PRODUCTION METHOD FOR NEURON-LIKE CELLS
  申请人：Kataoka Corporation

  公开号：EP3822343A1

  公开（公告）日：2021-05-19

  It is a main object of the present invention to provide a process for producing a neuron-like cell from a somatic cell, a neuron-like cell obtained thereby, and a composition comprising a combination of chemical substances that can be used for said process without performing artificial gene transfer. The invention can include, for example, a process for producing neuron-like cells, characterized by comprising a step of culturing somatic cells in the presence of two kinds of inhibitors, i.e., a TGF-β inhibitor and a BMP inhibitor, as well as any three or more selected from the group consisting of four kinds, i.e., a cAMP inducer, a GSK3 inhibitor, an Erk-inhibitor, and a p53-inhibitor, wherein the TGF-β inhibitor is a selective ALK5 inhibitor, and a neuron-like cell obtained by said process. The neuron-like cells obtained according to the present invention are useful in regenerative medicine and the like.

  本发明的主要目的是提供一种从体细胞生产神经元样细胞的工艺、由此获得的神经元样细胞，以及一种包含化学物质组合的组合物，该组合物可用于上述工艺而无需进行人工基因转移。 例如，本发明可包括一种生产神经元样细胞的工艺，其特征在于包括在两种抑制剂（即）存在下培养体细胞的步骤、TGF-β抑制剂和BMP抑制剂，以及选自四种抑制剂（即cAMP诱导剂、GSK3抑制剂、Erk抑制剂和p53抑制剂）组中的任意三种或更多种，其中TGF-β抑制剂为选择性ALK5抑制剂，以及通过所述工艺获得的神经元样细胞。 根据本发明获得的神经元样细胞可用于再生医学等领域。
• METHOD FOR PRODUCING INSULIN-PRODUCING CELLS, AND COMPOSITION
  申请人：Kataoka Corporation

  公开号：EP3882340A1

  公开（公告）日：2021-09-22

  It is a main object of the present invention to provide a new producing method capable of efficiently performing direct conversion or induction from a somatic cell to an insulin-producing cell. The present invention can include, for example, a process for producing an insulin-producing cell by direct differentiation induction from a somatic cell, comprising a step of culturing a somatic cell in a serum-free differentiation induction medium, or a step of culturing a somatic cell in a differentiation induction medium containing 5 µg/mL or more of insulin. According to the present invention, insulin-producing cells having a high insulin secretion ability can be produced directly and efficiently from a somatic cell. The insulin-producing cells obtained according to the present invention are useful in regenerative medicine and the like.

  本发明的主要目的是提供一种新的生产方法，能够有效地将体细胞直接转化或诱导为胰岛素生产细胞。例如，本发明可包括通过从体细胞直接分化诱导产生胰岛素分泌细胞的工艺，包括在无血清分化诱导培养基中培养体细胞的步骤，或在含有 5 µg/mL 或更多胰岛素的分化诱导培养基中培养体细胞的步骤。根据本发明，可直接有效地从体细胞制备出具有高胰岛素分泌能力的胰岛素分泌细胞。根据本发明获得的胰岛素分泌细胞可用于再生医学等领域。