4-(2-(oxiran-2-yl)ethoxy)carbazole | 955371-83-2

• 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: 4-(2-(oxiran-2-yl)ethoxy)carbazole
• 英文别名: 4-[2-(oxiran-2-yl)ethoxy]-9H-carbazole
• CAS: 955371-83-2
• 化学式: C₁₆H₁₅NO₂
• 分子量: 253.301
• InChiKey: MNDAHGZSSAYZDF-UHFFFAOYSA-N

物化性质

• 沸点：
  470.9±15.0 °C(Predicted)
• 密度：
  1.287±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  37.6
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-(2-(oxiran-2-yl)ethoxy)carbazole 在 三乙胺 、 lithium bromide 作用下， 以 乙二醇二甲醚 、 氯仿 为溶剂， 反应 6.0h， 生成
  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-溴-1,2-环氧丁烷 、 4-羟基咔唑 在 sodium hydroxide 作用下， 以 水 、 二甲基亚砜 为溶剂， 反应 24.0h， 以61%的产率得到4-(2-(oxiran-2-yl)ethoxy)carbazole
  参考文献：
  名称：

  Ryanodine receptor inhibitors and methods relating thereto

  摘要：

  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。

  公开号：

  US20070254849A1

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。
• 一种咔唑β-氨基醇类衍生物及其制备方法和 用途
  申请人：南方医科大学

  公开号：CN109867662B

  公开（公告）日：2020-08-14

  本发明涉及一种咔唑β‑氨基醇类衍生物，其药物组合物、制备方法及用途。本发明化合物能够有效的抑制toll样受体4的活性及水平和对HCN通道亚型有抑制作用，其中具体公开了6种化合物，并公开了所述的化合物及其可药用接受的盐在制备TLR4受体抑制剂及应用为佐剂、抗炎、肿瘤免疫等方面的应用。其结构如下式所示：其中R1为取代的卤素原子、氨基、硝基、C1‑6烷基、C1‑6烷氧基，和C1‑6烷基中任意一个或多个取代基所取代，R2为取代的H，卤素原子、氨基、硝基、C1‑6烷基、C1‑6烷氧基，和C1‑6烷基中任意一个或多个取代基所取代。n为1，2，3或4。
• Discovery of novel small molecule TLR4 inhibitors as potent anti-inflammatory agents
  作者：Yao Xu、Shujun Chen、Ying Cao、Pingzheng Zhou、Zhipeng Chen、Kui Cheng

  DOI：10.1016/j.ejmech.2018.05.033

  日期：2018.6

  Toll-like receptor 4 (TLR4) initiates innate immune response to release inflammatory cytokines and has been pathologically linked to variety of inflammatory diseases. Recently, we found that Carvedilol, as the classic anti-heart failure and anti-inflammatory clinic drug, could inhibit the TLR4 signaling in the TLR4 overexpressed cells. Herein, we have designed and synthesized a small library of novel Carvedilol derivatives and investigated their potential inhibitory activity. The results indicate that the most potent compound 8a (SMU-XY3) could effectively inhibited TLR4 protein and the LPS triggered alkaline phosphatase signaling in HEK-Blue hTLR4 cells. It down regulated the nitric oxide (NO) in both RAW264.7 cells and BV-2 microglial cells, in addition to blocking the TNF-alpha signaling in ex-vivo human peripheral blood mononuclear cells (PBMC). More interestingly, 8a shows higher affinity to hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) over HCN2, which probably indicates the new application of TLR4 inhibitor 8a in heart failure, coronary heart disease, and other inflammatory diseases. (C) 2018 Elsevier Masson SAS. All rights reserved.
• A carvedilol analogue, VK‐II‐86, prevents hypokalaemia‐induced ventricular arrhythmia through novel multi‐channel effects
  作者：Victoria M. Robinson、Izzeddin Alsalahat、Sally Freeman、Charles Antzelevitch、Héctor Barajas‐Martinez、Luigi Venetucci

  DOI：10.1111/bph.15775

  日期：2022.6

  Background and PurposeQT prolongation and intracellular Ca2+ loading with diastolic Ca2+ release via ryanodine receptors (RyR2) are the predominant mechanisms underlying hypokalaemia‐induced ventricular arrhythmia. We investigated the antiarrhythmic actions of two RyR2 inhibitors: dantrolene and VK‐II‐86, a carvedilol analogue lacking antagonist activity at β‐adrenoceptors, in hypokalaemia.Experimental ApproachSurface ECG and ventricular action potentials (APs) were recorded from whole‐heart murine Langendorff preparations. Ventricular arrhythmia incidence was compared in hearts perfused with low [K+], and those pretreated with dantrolene or VK‐II‐86. Whole‐cell patch clamping was used in murine and canine ventricular cardiomyocytes to study effects of dantrolene and VK‐II‐86 on AP parameters in low [K+] and effects of VK‐II‐86 on the inward rectifier current (IK1), late sodium current (INa_L) and the L‐type Ca2+ current (ICa). Effects of VK‐II‐86 on IKr were investigated in transfected HEK‐293 cells. A fluorogenic probe quantified the effects of VK‐II‐86 on oxidative stress in hypokalaemia.Key ResultsDantrolene reduced the incidence of ventricular arrhythmias induced by low [K+] in explanted murine hearts by 94%, whereas VK‐II‐86 prevented all arrhythmias. VK‐II‐86 prevented hypokalaemia‐induced AP prolongation and depolarization but did not alter AP parameters in normokalaemia. Hypokalaemia was associated with decreased IK1 and IKr, and increased INa‐L, and ICa. VK‐II‐86 prevented all hypokalaemia‐induced changes in ion channel activity and oxidative stress.Conclusions and ImplicationsVK‐II‐86 prevents hypokalaemia‐induced arrhythmogenesis by normalizing calcium homeostasis and repolarization reserve. VK‐II‐86 may provide an effective treatment in hypokalaemia and other arrhythmias caused by delayed repolarization or Ca2+ overload.