4-(3,4-dihydro-2(1H)-isoquinolinylcarbonyl)-N-[4-(methyloxy)phenyl]-1,3-thiazol-2-amine | 736945-96-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 4-(3,4-dihydro-2(1H)-isoquinolinylcarbonyl)-N-[4-(methyloxy)phenyl]-1,3-thiazol-2-amine
• 英文别名: GSK417651A；3,4-dihydro-1H-isoquinolin-2-yl-[2-(4-methoxyanilino)-1,3-thiazol-4-yl]methanone
• CAS: 736945-96-3
• 化学式: C₂₀H₁₉N₃O₂S
• 分子量: 365.456
• InChiKey: NTXBDULODNTCKP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  82.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  对甲氧基苯基硫脲 在 甲醇 、 乙醇 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.5h， 生成 4-(3,4-dihydro-2(1H)-isoquinolinylcarbonyl)-N-[4-(methyloxy)phenyl]-1,3-thiazol-2-amine
  参考文献：
  名称：

  The discovery of potent blockers of the canonical transient receptor channels, TRPC3 and TRPC6, based on an anilino-thiazole pharmacophore

  摘要：

  Lead optimization of piperidine amide HTS hits, based on an anilino-thiazole core, led to the identification of analogs which displayed low nanomolar blocking activity at the canonical transient receptor channels 3 and 6 (TRPC3 & 6) based on FLIPR (carbachol stimulated) and electrophysiology (OAG stimulated) assays. In addition, the anilino-thiazole amides displayed good selectivity over other TRP channels (TRPA1, TRPV1, and TRPV4), as well as against cardiac ion channels (CaV1.2, hERG, and NaV1.5). The high oxidation potential of the aliphatic piperidine and aniline groups, as well as the lability of the thiazole amide group contributed to the high clearance observed for this class of compounds. Conversion of an isoquinoline amide to a naphthyridine amide markedly reduced clearance for the bicyclic piperidines, and improved oral bioavailability for this compound series, however TRPC3 and TRPC6 blocking activity was reduced substantially. Although the most potent anilino-thiazole amides ultimately lacked oral exposure in rodents and were not suitable for chronic dosing, analogs such as 14-19, 22, and 23 are potentially valuable in vitro tool compounds for investigating the role of TRPC3 and TRPC6 in cardiovascular disease. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2013.06.047

文献信息

• [EN] COMPOUNDS<br/>[FR] COMPOSÉS
  申请人：GLAXOSMITHKLINE LLC

  公开号：WO2012037351A1

  公开（公告）日：2012-03-22

  Compounds, pharmaceutical compositions containing them, and their use treatment of conditions mediated by the TRPC3 and/or TRPC6 ion channels.

  化合物，含有它们的制药组合物，以及它们用于治疗由TRPC3和/或TRPC6离子通道介导的疾病的用途。
• [EN] ADMINISTRATION OF CALCIUM CHANNEL TRPC6 INHIBITORS USING BALLOONS, STENTS OR OTHER MEDICAL DEVICES<br/>[FR] ADMINISTRATION D'INHIBITEURS CALCIQUE TRPC6 À L'AIDE DE BALLONNETS, D'ENDOPROTHÈSES OU D'AUTRES DISPOSITIFS MÉDICAUX
  申请人：KLINIKUM RECHTS DER ISAR

  公开号：WO2021160625A1

  公开（公告）日：2021-08-19

  The present invention relates to a medical device suitable for being inserted into the lumen of an anatomic structure of a subject, said medical device comprising means for administration of TRPC6 inhibitor, wherein said means comprises the TRPC6 inhibitor. The present invention further concerns a method of manufacturing a medical device suitable for being inserted into the lumen of an anatomic structure of a subject. Also, the invention relates to a TRPC6 inhibitor for use in the treatment or prevention of a disease associated with neointimal hyperplasia associated with the migration of smooth muscular cells. The invention also relates to a method of treating or preventing a disease associated with neointimal hyperplasia, said method comprising administering a TRPC6 inhibitor to a subject in need thereof. Also envisaged is a method of inhibiting migration of smooth muscle cells. The invention additionally relates to an in vitro test kit comprising: (a) small muscle cells (SMCs); (b) a surface suitable for SMC cultivation coated with a TRPC6 inhibitor. Also concerned is a pharmaceutical composition comprising a TRPC6 inhibitor and a pharmaceutically acceptable carrier.
• The discovery of potent blockers of the canonical transient receptor channels, TRPC3 and TRPC6, based on an anilino-thiazole pharmacophore
  作者：David G. Washburn、Dennis A. Holt、Jason Dodson、Jeff J. McAtee、Lamont R. Terrell、Linda Barton、Sharada Manns、Anna Waszkiewicz、Christina Pritchard、Dan J. Gillie、Dwight M. Morrow、Elizabeth A. Davenport、Irina M. Lozinskaya、Jeffrey Guss、Jonathan B. Basilla、Lorena Kallal Negron、Michael Klein、Robert N. Willette、Rusty E. Fries、Timothy C. Jensen、Xiaoping Xu、Christine G. Schnackenberg、Joseph P. Marino

  DOI：10.1016/j.bmcl.2013.06.047

  日期：2013.9

  Lead optimization of piperidine amide HTS hits, based on an anilino-thiazole core, led to the identification of analogs which displayed low nanomolar blocking activity at the canonical transient receptor channels 3 and 6 (TRPC3 & 6) based on FLIPR (carbachol stimulated) and electrophysiology (OAG stimulated) assays. In addition, the anilino-thiazole amides displayed good selectivity over other TRP channels (TRPA1, TRPV1, and TRPV4), as well as against cardiac ion channels (CaV1.2, hERG, and NaV1.5). The high oxidation potential of the aliphatic piperidine and aniline groups, as well as the lability of the thiazole amide group contributed to the high clearance observed for this class of compounds. Conversion of an isoquinoline amide to a naphthyridine amide markedly reduced clearance for the bicyclic piperidines, and improved oral bioavailability for this compound series, however TRPC3 and TRPC6 blocking activity was reduced substantially. Although the most potent anilino-thiazole amides ultimately lacked oral exposure in rodents and were not suitable for chronic dosing, analogs such as 14-19, 22, and 23 are potentially valuable in vitro tool compounds for investigating the role of TRPC3 and TRPC6 in cardiovascular disease. Published by Elsevier Ltd.