1-(9H-carbazol-4-yloxy)-3-{[2-(4,5-dichloro-2-methoxyphenoxy)ethyl]amino}-2-propanol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 1-(9H-carbazol-4-yloxy)-3-{[2-(4,5-dichloro-2-methoxyphenoxy)ethyl]amino}-2-propanol
• 英文别名: 1-(9H-carbazol-4-yloxy)-3-[2-(4,5-dichloro-2-methoxyphenoxy)ethylamino]propan-2-ol
• 化学式: C₂₄H₂₄Cl₂N₂O₄
• 分子量: 475.372
• InChiKey: JTXDSXRWCSJQLB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  32
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  75.7
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(9H-carbazol-4-yloxy)-3-{[2-(4,5-dichloro-2-methoxyphenoxy)ethyl]amino}-2-propanol 在 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 、 氯仿 为溶剂， 反应 18.0h， 生成 6-[(9H-carbazol-4-yloxy)methyl]-4-[2-(4,5-dichloro-2-methoxyphenoxy)ethyl]-3-morpholinone
  参考文献：
  名称：

  Novel Carvedilol Analogues That Suppress Store-Overload-Induced Ca²⁺ Release

  摘要：

  Carvedilol is a uniquely effective drug for the treatment of cardiac arrhythmias in patients with heart failure. This activity is in part because of its ability to inhibit store-overload-induced calcium release (SOICR) through the RyR2 channel. We describe the synthesis, characterization, and bioassay of ca. 100 compounds based on the carvedilol motif to identify features that correlate with and optimize SOICR inhibition. A single-cell bioassay was employed on the basis of the RyR2-R4496C mutant HEK-293 cell line in which calcium release from the endoplasmic reticulum through the defective channel was measured. IC50 values for SOICR inhibition were thus obtained. The compounds investigated contained modifications to the three principal subunits of carvedilol, including the carbazole and catechol moieties, as well as the linker chain containing the beta-amino alcohol functionality. The SAR results indicate that significant alterations are tolerated in each of the three subunits.

  DOI：

  10.1021/jm401090a
• 作为产物：
  描述：

  、 4-环氧丙烷氧基咔唑 以 异丙醇 为溶剂， 反应 2.0h， 以62%的产率得到1-(9H-carbazol-4-yloxy)-3-{[2-(4,5-dichloro-2-methoxyphenoxy)ethyl]amino}-2-propanol
  参考文献：
  名称：

  Novel Carvedilol Analogues That Suppress Store-Overload-Induced Ca²⁺ Release

  摘要：

  Carvedilol is a uniquely effective drug for the treatment of cardiac arrhythmias in patients with heart failure. This activity is in part because of its ability to inhibit store-overload-induced calcium release (SOICR) through the RyR2 channel. We describe the synthesis, characterization, and bioassay of ca. 100 compounds based on the carvedilol motif to identify features that correlate with and optimize SOICR inhibition. A single-cell bioassay was employed on the basis of the RyR2-R4496C mutant HEK-293 cell line in which calcium release from the endoplasmic reticulum through the defective channel was measured. IC50 values for SOICR inhibition were thus obtained. The compounds investigated contained modifications to the three principal subunits of carvedilol, including the carbazole and catechol moieties, as well as the linker chain containing the beta-amino alcohol functionality. The SAR results indicate that significant alterations are tolerated in each of the three subunits.

  DOI：

  10.1021/jm401090a

文献信息

• [EN] STORE OVERLOAD-INDUCED CALCIUM RELEASE INHIBITORS AND METHODS FOR PRODUCING AND USING THE SAME<br/>[FR] INHIBITEURS DE LIBÉRATION DU CALCIUM INDUITE PAR UNE SURCHARGE DU STOCK CALCIQUE ET LEURS MÉTHODES DE PRODUCTION ET D'UTILISATION
  申请人：UTI LIMITED PARTNERSHIP

  公开号：WO2015031914A1

  公开（公告）日：2015-03-05

  The present invention provides compounds having store overload-induced Ca2+ release (SOICR) inhibitory activity and methods for producing and using the same. In particular, compounds of the invention is of the formula: R1-X1-L-X2-R2, wherein R1, X1, L, X2, and R2 are those defined herein.

  本发明提供了具有存储过载诱导的Ca2+释放（SOICR）抑制活性的化合物以及生产和使用这些化合物的方法。特别是，本发明的化合物具有如下通式：R1-X1-L-X2-R2，其中R1、X1、L、X2和R2如本文所定义。
• Ryanodine receptor inhibitors and methods relating thereto
  申请人：Chen Wayne S.R.

  公开号：US20070254849A1

  公开（公告）日：2007-11-01

  The present invention provides novel ryanodine receptor type 2 (RyR2) inhibitors and methods of their use in the treatment of cardiac conditions. In general, the RyR2 inhibitors of the present invention assist in the normalization of intracellular calcium homeostasis. In certain embodiments, the RyR2 inhibitors are store-overload-induced Ca 2+ release (SOICR) inhibitors that minimally inhibit or do not inhibit Ca 2+ -induced Ca 2+ release (CICR), thereby providing beneficial effects in cardiac therapy.

  本发明提供了新颖的Ryanodine受体类型2（RyR2）抑制剂及其在治疗心脏疾病中的使用方法。一般而言，本发明的RyR2抑制剂有助于使细胞内钙离子稳态正常化。在某些实施例中，RyR2抑制剂是储存超载诱导的Ca2+释放（SOICR）抑制剂，最小程度地抑制或不抑制Ca2+诱导的Ca2+释放（CICR），从而在心脏治疗中提供有益效果。
• STORE OVERLOAD-INDUCED CALCIUM RELEASE INHIBITORS AND METHODS FOR PRODUCING AND USING THE SAME
  申请人：BACK Tom

  公开号：US20160214973A1

  公开（公告）日：2016-07-28

  The present invention provides compounds having store overload-induced Ca 2+ release (SOICR) inhibitory activity and methods for producing and using the same. In particular, compounds of the invention is of the formula: R 1 —X 1 -L-X 2 —R 2 , wherein R 1 , X 1 , L, X 2 , and R 2 are those defined herein.
• US8703804B2
  申请人：——

  公开号：US8703804B2

  公开（公告）日：2014-04-22
• [EN] RYANODINE RECEPTOR INHIBITORS AND METHODS RELATING THERETO<br/>[FR] INHIBITEURS DU RÉCEPTEUR DE LA RYANODINE ET PROCÉDÉS ASSOCIÉS
  申请人：UTI LIMITED PARTNERSHIP

  公开号：WO2007144785A2

  公开（公告）日：2007-12-21

  [EN] The present invention provides novel ryanodine receptor type 2 (RyR2) inhibitors and methods of their use in the treatment of cardiac conditions. In general, the RyR2 inhibitors of the present invention assist in the normalization of intracellular calcium homeostasis. In certain embodiments, the RyR2 inhibitors are store-overload-induced Ca²⁺ release (SOICR) inhibitors that minimally inhibit or do not inhibit Ca²⁺-induced Ca²⁺ release (CICR), thereby providing beneficial effects in cardiac therapy.
  [FR] La présente invention concerne de nouveaux inhibiteurs du récepteur de type 2 de la ryanodine (RyR2) et des procédés d'utilisation de ceux-ci pour le traitement de pathologies cardiaques. En général, les inhibiteurs du RyR2 de la présente invention favorisent la normalisation de l'homéostase calcique intracellulaire. Dans certains modes de réalisation, les inhibiteurs du RyR2 sont des inhibiteurs de la libération de Ca²⁺ induite par une surcharge de réserve (LCISR) qui inhibent au minimum ou n'inhibent pas la libération de Ca²⁺ induite par le Ca²⁺ (LCIC), ce qui produit des effets bénéfiques sur une thérapie cardiaque.