3-chloro-N-[4-(methylamino)cyclohexyl]-N-[(3-pyridin-4-ylphenyl)methyl]-1-benzothiophene-2-carboxamide | 912545-86-9

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-chloro-N-[4-(methylamino)cyclohexyl]-N-[(3-pyridin-4-ylphenyl)methyl]-1-benzothiophene-2-carboxamide
• 英文别名: SAG；smoothened agonist；3-chloro-N-[trans-4-(methylamino)cyclohexyl]-N-[[3-(4-pyridinyl)phenyl]methyl]benzo[b]thiophene-2-carboxamide；SAG-1.3；[3H]SAG-1.3
• CAS: 912545-86-9
• 化学式: C₂₈H₂₈ClN₃OS
• 分子量: 490.069
• InChiKey: VFSUUTYAEQOIMW-YHBQERECSA-N

物化性质

• 沸点：
  688.6±55.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于 DMSO（高达 20 mg/ml）、DMF（高达 20 mg/ml）或乙醇（高达 20 mg/ml）。

计算性质

• 辛醇/水分配系数(LogP)：
  6.79
• 重原子数：
  34.0
• 可旋转键数：
  6.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  45.23
• 氢给体数：
  1.0
• 氢受体数：
  4.0

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

SAG 是一种有效的 SMOothened (SMO) 受体激动剂（EC50=3 nM；Kd=59 nM）。SAG 可激活 Hedgehog 信号通路并抵消 Cyclopamine 对 SMO 的抑制作用。

靶点

• EC50: 3 nM (SMO)

体外研究

1. SAG（0.1 nM-100 μM；30 h）诱导 Shh-LIGHT2 细胞中萤火虫荧光素酶表达，EC50 为 3 nM，并在更高浓度时抑制其表达。
2. SAG（1-1000 nM；1 h）与 SMO 表达的 Cos-1 细胞竞争结合 BODIPY-cyclopamine，SAG/SMO 复合物的解离常数 (Kd) 为 59 nM。
3. SAG（100 nM）抑制 Robotnikinin 引起的 Hedgehog 信号通路激活。
4. SAG（250 nM；48 h）显著增加 MDAMB231 细胞中 SMO 基因和蛋白的表达。
5. 在常氧和缺氧条件下，SAG（250 nM；24 和 48 h）在 24 小时后显著增加 MDAMB231 细胞中 CAXII mRNA 的表达。
6. SAG（250 nM；24 h）促进 MDAMB231 细胞迁移。

体内研究

1. SAG（1.0 mM）在 CD-1 小鼠的缺陷边界处诱导更多的骨形成，并在八周时显著增加 BV/TV。
2. SAG（15-20 mg/kg；腹腔注射）以剂量依赖性方式在小鼠中诱导前轴多指畸形。

动物模型：	哺乳动物
用药剂量：	15, 17, 20 mg/kg
给药途径：	单次腹腔注射
结果：	在约 80% 的胚胎中有效，并且在 20 mg/kg 剂量下 Gli1 和 Gli2 mRNA 表达增加，其中 Gli1 mRNA 上调最为显著。

反应信息

• 作为反应物：
  描述：

  3-chloro-N-[4-(methylamino)cyclohexyl]-N-[(3-pyridin-4-ylphenyl)methyl]-1-benzothiophene-2-carboxamide 、 Tert-butyl 4-[2-methoxy-5-nitro-4-[1-(4-nitrophenoxy)carbonyloxyethyl]phenoxy]butanoate 在 盐酸 作用下， 以 N,N-二甲基甲酰胺 、 水 为溶剂， 以45%的产率得到
  参考文献：
  名称：

  A Light-Inducible Hedgehog Signaling Activator Modulates Proliferation and Differentiation of Neural Cells

  摘要：

  The Hedgehog signaling pathway shapes our body by regulating the proliferation and differentiation of cells. The spatial and temporal distribution pattern of its ligands finely controls the activity of the Hedgehog pathway during development. To model the control of Hedgehog signaling activities in vitro, we developed a light-inducible Hedgehog signaling activator 6-nitroveratryloxy-carbonyl Smoothened agonist (NVOC-SAG). NVOC-SAG controls the proliferation of mouse cerebellar granule neuron precursor cells and ventral and neural differentiation of human iPS cells in a light dependent manner. The compound provides a new method to control Hedgehog signaling activities.

  DOI：

  10.1021/acschembio.0c00195
• 作为产物：
  描述：

  tert-butyl ((1r,4r)-4-(3-chloro-N-(3-(pyridin-4-yl)benzyl)benzo[b]thiophene-2-carboxamido)cyclohexyl)(methyl)carbamate 在 盐酸 作用下， 以 乙醇 、 水 为溶剂， 反应 3.0h， 生成 3-chloro-N-[4-(methylamino)cyclohexyl]-N-[(3-pyridin-4-ylphenyl)methyl]-1-benzothiophene-2-carboxamide
  参考文献：
  名称：

  Potent agonists of the Hedgehog signaling pathway

  摘要：

  A family of biaryl substituted 1,4-diaminocyclohexanamides of 3-chlorobenzothiophene-2-carboxylic acid is reported as picomolar modulators of Hedgehog protein function. SAR for the 1,4-diaminocyclohexane group is shown to be exquisitely sensitive to substitution on the 4-amino group, and SAR for the 3-chlorobenzothiophene group is highly specific Preliminary SAR studies of the biaryl substituent led to a picomolar compound with in vivo activity. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.05.096

文献信息

• Novel Compounds Modulating The Hedgehog Protein Signaling Pathway, Marked Forms Thereof, And Applications
  申请人：Centre National De La Recherche Scientifique

  公开号：US20140228441A1

  公开（公告）日：2014-08-14

  The invention relates to compounds of formula (I), and the use thereof as a drug, particularly for the treatment of tumors associated with hyperactivation of the hedgehog protein signaling pathway, treatment of neurodegenerative diseases, treatment of diseases related to cerebral development (holoprosencephaly), for stem cell monitoring treatment of cerebrovascular accidents and cardiovascular accidents, treatment of diseases involving oligodendrocytes and diseases involving neurolemmocytes, for application thereof in vitro for modulating human or animal stem cell renewal, and for the treatment of diabetes. The invention also relates to pharmaceutical compositions having a compound of formula (I). The invention also relates to a method for radio-marking compounds having formula (I), the marked compounds, and the use of the compounds as research tools, and method for screening and/or identifying ligands in the Smoothened receptor (Smo) binding sites, methods for identifying agonists and antagonists of the Smoothened receptor, and a method for identifying cells.

  该发明涉及式(I)的化合物，以及其作为药物的用途，特别是用于治疗与刺刺蛋白信号通路的高活化相关的肿瘤，治疗神经退行性疾病，治疗与脑发育相关的疾病（全脑前脑发育不全），用于干细胞监测治疗脑血管事故和心血管事故，治疗涉及寡脂髓细胞和涉及神经鞘细胞的疾病，用于体外应用以调节人类或动物干细胞更新，并用于治疗糖尿病。该发明还涉及具有式(I)化合物的药物组合物。该发明还涉及一种标记具有式(I)的化合物的方法，标记的化合物，以及将化合物用作研究工具的用途，以及筛选和/或识别Smoothened受体（Smo）结合位点中配体的方法，识别Smoothened受体的激动剂和拮抗剂的方法，以及识别细胞的方法。
• METHOD FOR PRODUCING ADENOHYPOPHYSIS OR PRECURSOR TISSUE THEREOF
  申请人：RIKEN

  公开号：EP3954763A1

  公开（公告）日：2022-02-16

  The present invention provides a method for inducing adenohypophysis or precursor tissue thereof in vitro from human pluripotent stem cells. The method includes culturing an aggregate of human pluripotent stem cells in suspension in a medium containing a bone morphogenetic protein signal transduction pathway activating substance and a substance acting on the Shh signal pathway to obtain a human cell aggregate containing a hypothalamus neuroepithelial tissue and a surface ectoderm, and further culturing the obtained human cell aggregate containing the hypothalamus neuroepithelial tissue and the surface ectoderm in suspension in a medium containing a bone morphogenetic protein signal transduction pathway activating substance and a substance acting on the Shh signal pathway to induce formation of hypophysial placode and/or Rathke's pouch in the surface ectoderm, thus obtaining a human cell aggregate containing 1) hypothalamus neuroepithelial tissue, and 2) hypophysial placode and/or Rathke's pouch.

  本发明提供了一种从人多能干细胞体外诱导腺嗜析出或其前体组织的方法。该方法包括在含有骨形态发生蛋白信号转导通路激活物质和作用于Shh信号通路的物质的培养基中培养悬浮的人多能干细胞聚集体，以获得含有下丘脑神经上皮组织和表面外胚层的人细胞聚集体、在含有骨形态发生蛋白信号转导通路激活物质和作用于 Shh 信号通路的物质的培养基中，进一步悬浮培养所获得的包含下丘脑神经上皮组织和表面外胚层的人体细胞聚集体，以诱导表面外胚层形成下生理学胎盘和/或 Rathke's pouch，从而获得包含 1) 下丘脑神经上皮组织和 2) 下生理学胎盘和/或 Rathke's pouch 的人体细胞聚集体。
• Functional oligodendrocytes derived from pluripotent stem cells and methods of making and using the same
  申请人：New York Stem Cell Foundation, Inc.

  公开号：US10301592B2

  公开（公告）日：2019-05-28

  Described is the efficient and robust generation of oligodendrocyte progenitor cells (OPCs) and oligodendrocytes from pluripotent stem cells (PSCs). The protocols provided recapitulate the major steps of oligodendrocyte differentiation, from neural stem cells to OLIG2+progenitors, and then to 04+ OPCs, in a significantly shorter time than the 120-150 days required by previous protocols. Furthermore, 04+ OPCs are able to differentiate into MBP+mature oligodendrocytes in vitro, and to myelinate axons in vivo when injected into immuno-compromised Shiverer mice, providing proof of concept that transplantation of PSC-derived cells for remyelination is technically feasible.

  描述了从多能干细胞（PSCs）高效、稳健地生成少突胶质祖细胞（OPCs）和少突胶质细胞的过程。所提供的方案再现了少突胶质细胞分化的主要步骤，即从神经干细胞到 OLIG2+ 祖细胞，再到 04+ OPCs，所需的时间大大短于以往方案所需的 120-150 天。此外，04+ OPCs 还能在体外分化成 MBP+ 成熟少突胶质细胞，并在注射到免疫受损的 Shiverer 小鼠体内使轴突髓鞘化，这证明了移植 PSC 衍生细胞进行再髓鞘化在技术上是可行的。
• Methods for differentiating pluripotent cells
  申请人：FUJIFILM Cellular Dynamics, Inc.

  公开号：US10590383B2

  公开（公告）日：2020-03-17

  Methods are provided, in some aspects, for differentiating pluripotent cells into midbrain dopaminergic (DA) neurons using a mono-SMAD inhibition or inhibition of SMAD signaling with only one SMAD inhibitor. In some embodiments, mono-SMAD inhibition utilizes a single inhibitor of bone morphogenic protein (BMP) for differentiating pluripotent cells into midbrain DA neurons.

  在某些方面，提供了使用单SMAD抑制剂或仅用一种SMAD抑制剂抑制SMAD信号传导将多能细胞分化成中脑多巴胺能（DA）神经元的方法。在一些实施方案中，单-SMAD 抑制利用单一的骨形态发生蛋白（BMP）抑制剂将多能细胞分化成中脑 DA 神经元。
• Treatment of demyelinating diseases
  申请人：M ET P PHARMA AG

  公开号：US10596181B2

  公开（公告）日：2020-03-24

  Described herein are methods of promoting remyelination in a subject suffering from demyelination diseases by administering to the subject a combination of steroid hormones and Hedgehog signaling pathway modulators. Also described are methods of administering the combination of drugs, wherein the combination of drugs are in compositions adapted for nasal administration.

  本文描述了通过对患有脱髓鞘疾病的受试者施用类固醇激素和刺猬信号通路调节剂的组合药物来促进其脱髓鞘再形成的方法。还描述了施用药物组合的方法，其中药物组合为适于鼻腔给药的组合物。