N-{4-[5-(4-fluoro-phenyl)-3-methyl-2-methylsulfinyl-3H-imidazol-4-yl]-pyridin-2-yl}-acetamide | 908380-97-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-{4-[5-(4-fluoro-phenyl)-3-methyl-2-methylsulfinyl-3H-imidazol-4-yl]-pyridin-2-yl}-acetamide
• 英文别名: N-(4-(4-(4-fluorophenyl)-1-methyl-2-(methylsulfinyl)-1H-imidazol-5-yl)pyridin-2-yl)acetamide；CBS-3595；N-{4-[5-(4-fluorophenyl)-2-methanesulfinyl-3-methyl-3H-imidazol-4-yl]pyridin-2-yl}acetamide；N-[4-[5-(4-fluorophenyl)-3-methyl-2-methylsulfinylimidazol-4-yl]pyridin-2-yl]acetamide
• CAS: 908380-97-2；908381-23-7；908382-07-0
• 化学式: C₁₈H₁₇FN₄O₂S
• 分子量: 372.423
• InChiKey: DRMJRHUMYBYDIX-UHFFFAOYSA-N

物化性质

• 密度：
  1.38±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  96.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-{4-[5-(4-fluoro-phenyl)-3-methyl-2-methylsulfinyl-3H-imidazol-4-yl]-pyridin-2-yl}-acetamide 在 氢溴酸 作用下， 以 四氢呋喃 为溶剂， 以98%的产率得到N-{4-[5-(4-fluorophenyl)-2-methanesulfinyl-3-methyl-3H-imidazol-4-yl]pyridin-2-yl}acetamide hydrobromide
  参考文献：
  名称：

  WO2006/89798

  摘要：

  公开号：
• 作为产物：
  描述：

  2-(乙酰氨基)-4-甲基吡啶 在 potassium permanganate 、 2,2,4,4-tetramethyl-3-thioxocyclobutanone 、 氢溴酸 、 双氧水 、 溶剂黄146 、 N,N'-羰基二咪唑 、 亚硝酸异戊酯 作用下， 以 水 为溶剂， 生成 N-{4-[5-(4-fluoro-phenyl)-3-methyl-2-methylsulfinyl-3H-imidazol-4-yl]-pyridin-2-yl}-acetamide
  参考文献：
  名称：

  Discovery of N-{4-[5-(4-Fluorophenyl)-3-methyl-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-acetamide (CBS-3595), a Dual p38α MAPK/PDE-4 Inhibitor with Activity against TNFα-Related Diseases

  摘要：

  The anti-inflammatory potential of p38 mitogen-activated protein kinase (MAPK) inhibitors was coincidentally expanded to a dual inhibition of p38 alpha MAPK and phosphodiesterase 4 (PDE4), and the potential benefits arising from the blockage of both inflammation-related enzymes were thoroughly investigated. The most promising compound, CBS-3595 (1), was successively evaluated in in vitro experiments as well as in ex vivo and in vivo preclinical studies after administration of 1 to rodents, dogs, and monkeys. The resulting data clearly indicated a potent suppression of tumor necrosis factor alpha release. For reconfirming the findings of the animal studies when administering 1 to healthy human volunteers, a phase I clinical trial was conducted. Apart from further information regarding the pharmacokinetic and pharmacodynamic characteristics of 1, it was demonstrated that dual inhibition of p38 alpha MAPK and PDE4 is able to synergistically attenuate the excessive anti-inflammatory response.

  DOI：

  10.1021/acs.jmedchem.6b01647

文献信息

• 2-SULFINYL- AND 2-SULFONYL-SUBSTITUTED IMIDAZOLE DERIVATIVES AND THEIR USE AS CYTOKINE INHIBITORS
  申请人：Albrecht Wolfgang

  公开号：US20100273833A1

  公开（公告）日：2010-10-28

  The invention relates to 2-sulfinyl- or 2-sulfonyl-substituted imidazole derivatives of the formula (I) in which the radicals R 1 , R 2 , R 3 and R 4 have the meaning indicated in the description. The compounds of the invention have an immunomodulating and/or cytokine release-inhibiting effect and are therefore suitable for the treatment of disorders associated with an impairment of the immune system.

  本发明涉及式(I)的2-亚磺酰基或2-磺酰基取代的咪唑衍生物，其中基团R1、R2、R3和R4的含义如说明书所示。本发明的化合物具有免疫调节和/或细胞因子释放抑制作用，因此适用于治疗与免疫系统损伤有关的疾病。
• P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
  申请人：Fulcrum Therapeutics, Inc.

  公开号：US10342786B2

  公开（公告）日：2019-07-09

  The disclosure relates to methods and compositions including p38 kinase inhibitors and agents that regulate expression of DUX4 and downstream genes including but not restricted to ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, or ZNF280A. Methods useful for treating a disease associated with abnormal DUX4 and downstream gene expression (e.g., Fascioscapulohumeral muscular dystrophy) are disclosed.

  本发明公开了包括 p38 激酶抑制剂和调节 DUX4 及下游基因（包括但不限于 ZSCAN4、LEUTX、PRAMEF2、TRIM43、MBD3L2、KHDC1L、RFPL2、CCNA1、SLC34A2、TPRX1、PRAMEF20、TRIM49、PRAMEF4、PRAME6、PRAMEF15 或 ZNF280A）表达的制剂在内的方法和组合物。本研究公开了用于治疗与 DUX4 及下游基因表达异常有关的疾病（如筋膜囊性肌营养不良症）的方法。
• Chiral Sulfoxides as Metabolites of 2-Thioimidazole-Based p38α Mitogen-Activated Protein Kinase Inhibitors: Enantioselective Synthesis and Biological Evaluation
  作者：Stefanie Bühler、Marcia Goettert、Dieter Schollmeyer、Wolfgang Albrecht、Stefan A. Laufer

  DOI：10.1021/jm101623p

  日期：2011.5.12

  A number of pharmaceutically important drugs contain asymmetric sulfinyl moieties, so the biological evaluation of chiral sulfoxides as human drug metabolites is important for the development of safe and effective pharmaceuticals. Asymmetric oxidation is one of the most attractive ways to prepare chiral sulfoxides. In combination with different chiral ligands, the iron- and titanium-catalyzed asymmetric oxidations of tri- and tetrasubstituted 2-thioimidazoles afford the corresponding sulfoxides with enantiomeric excesses up to 99% as novel p38a mitogen-activated protein kinase (p38 alpha MAPK) inhibitors. The enantiomerically pure sulfoxides were evaluated on their inhibitory potency against p38 alpha MAPK compared to the respective sulfides and sulfoxide racemates and showed differences in their affinities for the enzyme with IC(50) in the low nanomolar range. In addition, the ability to inhibit the release of tumor necrosis factor-alpha (TNF-alpha) from human whole blood (HWB) was examined. Some pyridinylimidazole derivatives showed excellent HWB activity with IC(50) as low as 52 nM.
• P38 KINASE INHIBITORS REDUCE DUX4 AND DOWNSTREAM GENE EXPRESSION FOR THE TREATMENT OF FSHD
  申请人：Fulcrum Therapeutics, Inc.

  公开号：US20190105311A1

  公开（公告）日：2019-04-11

  The disclosure relates to methods and compositions including p38 kinase inhibitors and agents that regulate expression of DUX4 and downstream genes including but not restricted to ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, or ZNF280A. Methods useful for treating a disease associated with abnormal DUX4 and downstream gene expression (e.g., Facioscapulohumeral muscular dystrophy) are disclosed.
• [EN] 2-SULFINYL- AND 2-SULFONYL-SUBSTITUTED IMIDAZOLE DERIVATIVES AND THEIR USE AS CYTOKINE INHIBITORS<br/>[FR] DÉRIVÉS D'IMIDAZOLE DE 2-SULFINYLE ET DE 2-SULFONYLE ET LEUR UTILISATION COMME INHIBITEURS DE CYTOKINES
  申请人：MERCKLE GMBH

  公开号：WO2006089798A1

  公开（公告）日：2006-08-31

  [EN] The invention relates to 2-sulfinyl- or 2-sulfonyl-substituted imidazole derivatives of the formula (I) in which the radicals R¹, R², R³ and R⁴ have the meaning indicated in the description. The compounds of the invention have an immunomodulating and/or cytokine release-inhibiting effect and are therefore suitable for the treatment of disorders associated with an impairment of the immune system.
  [FR] La présente invention concerne des dérivés d'imidazole de 2-sulfinyle et de 2-sulfonyle de la formule (I) dans laquelle les radicaux R¹, R², R³ et R⁴ possèdent la signification indiquée dans la description. Les composés de l'invention présentent un effet immunomodulateur et/ou d'inhibition de libération des cytokines et, par conséquent, sont appropriés pour le traitement de désordres associés aux troubles du système immunitaire.