descyano-bimakalim | 220597-46-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: descyano-bimakalim
• 英文别名: 2(1H)-Pyridinone, 1-(2,2-dimethyl-2H-1-benzopyran-4-yl)-；1-(2,2-dimethylchromen-4-yl)pyridin-2-one
• CAS: 220597-46-6
• 化学式: C₁₆H₁₅NO₂
• 分子量: 253.301
• InChiKey: BUTIXGPZGLGTDG-UHFFFAOYSA-N

物化性质

• 熔点：
  114 °C
• 沸点：
  438.6±45.0 °C(Predicted)
• 密度：
  1.199±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  descyano-bimakalim 在 氯磺酸 作用下， 以 氯仿 为溶剂， 反应 0.5h， 以78%的产率得到descyano-bimakalim-6-sulfochloride
  参考文献：
  名称：

  6-磺酰基色烯作为高效的K（ATP）通道开放剂。

  摘要：

  我们合成了由Bimakalim（1）的4​​-吡啶酮亚甲基部分和各种含磺酰基的6-取代基4-29组成的K（ATP）通道开放剂（KCO）。测量大鼠主动脉和气管中的扩张器效能。在两个测试系统中，KCO的效能范围大约为3 log个单位。6-N-苯基-N-甲基磺酰胺基衍生物24显示出最高的效力。在大鼠主动脉中，效价谱的范围从8.76到5.68的pEC（50）值；在大鼠气管中，其范围为8.01至4.99。平均而言，主动脉中的扩张器活动增强约0.8 log个单位。色烯13的主动脉舒张作用明显受阻，其临床相关性（例如，预防心动过速）仍有待阐明。在大鼠的心肌膜和主动脉平滑肌细胞中测定结合亲和力。心肌膜的亲和光谱范围为7.83至5.18的pK（D）；对于化合物28（pK（D）= 8.55），在主动脉平滑肌细胞中测得的最高亲和力（pK（D）= 4.51），而对于化合物4（pK（D）= 4.51），则测得的最低

  DOI：

  10.1021/jm010999g
• 作为产物：
  描述：

  2,2,-二甲基-2H-苯并吡喃 在 吡啶 、 氢氧化钾 、 sodium hydroxide 、 N-溴代丁二酰亚胺(NBS) 作用下， 以 1,4-二氧六环 、 乙醚 、 乙醇 、 水 、 二甲基亚砜 为溶剂， 反应 50.5h， 生成 descyano-bimakalim
  参考文献：
  名称：

  6-Substituted Benzopyrans as Potassium Channel Activators:  Synthesis, Vasodilator Properties, and Multivariate Analysis

  摘要：

  During the last 10 years compounds have been discovered which can activate or block K-ATP channels. In particular, K channel activators (KCA)have been found to be smooth muscle relaxants with their main utility in hypertension and bronchodilation. In this paper we describe the synthesis of new KCA of the benzopyran type with a fixed 4-substituent and a systematic variation in the 6-position. The relaxant potency in rat aorta and trachea was used for biological characterization of the benzopyrans. In both biological test systems, they exhibit potency ranges of more than 3 log units. Structure-activity relationships are investigated by principal component analysis (PCA) and partial least-squares (PLS) analysis. Most striking outliers in an initial PLS analysis of the entire database were the unsubstituted 6-H compound 13 as well as 34 and 35. For the remaining set of 31 compounds, a S-component PLS model explains the variance in biological activity to 81% in the aortic and to 82% in the tracheal test system. 6-Substituents influence affinity by a direct (presumably dipolar) interaction with the receptor site. According to the 2D-plot of the partial PLS weights, a strong electronegativity as well as high values for the integy moment and for the heat of formation in water dominate the first component; low values for substituent size (as defined by globularity or surface) are in addition favorable for high potency. High lipophilicity and low minimum energies of interaction dominate the second component. Chemical descriptors for the biological potency of the test set in rat aorta and rat trachea are very similar according to the almost identical projection of the Y-variables onto the X-component space.

  DOI：

  10.1021/jm981047m

文献信息

• K_ATPchannel openers of the benzopyran type reach their binding site via the cytosol
  作者：D Stephan、E Salamon、H Weber、U Russ、H Lemoine、U Quast

  DOI：10.1038/sj.bjp.0706858

  日期：2006.9

  Background and purpose:ATP‐sensitive K+ (KATP) channels are composed of pore‐forming subunits (Kir6.x) and of sulphonylurea receptors (SUR). Both sulphonylureas and KATP channel openers act by binding to SUR. Sulphonylureas reach their binding site from the cytosol but it remains unknown whether this holds for openers too.Experimental approach:A poorly membrane‐permeant sulphonic acid derivative of the benzopyran‐type opener, bimakalim, was synthesized, descyano‐bimakalim‐6‐sulphonic acid (BMSA). Binding of BMSA and bimakalim was compared in membranes and intact cells expressing the Kir6.2/SUR2B channel and channel opening was compared in inside‐out patches and whole cells.Key results:In membranes, bimakalim and BMSA bound to Kir6.2/SUR2B with Ki values of 61 nM and 4.3 μM, showing that the negative charge decreased affinity 69‐fold. In intact cells, however, binding of BMSA was much weaker than in membranes (75‐fold) whereas that of bimakalim was unchanged. The Ki value of BMSA decreased with increasing incubation time. In inside‐out patches, bimakalim (1 μM) and BMSA (100 μM) opened the Kir6.2/SUR2B channel closed by MgATP to a similar degree whereas in whole‐cell experiments, only bimakalim was effective.Conclusions and implications:Despite its negative charge, BMSA is an effective channel opener. The fact that BMSA binds and acts more effectively when applied to the inner side of the cell membrane shows that benzopyran openers reach their binding site at SUR from the cytosol. This suggests that the binding pocket of SUR is only open on the cytoplasmic side.British Journal of Pharmacology (2006) 149, 199–205. doi:10.1038/sj.bjp.0706858
• US5387587A
  申请人：——

  公开号：US5387587A

  公开（公告）日：1995-02-07
• US6040308A
  申请人：——

  公开号：US6040308A

  公开（公告）日：2000-03-21
• US6153627A
  申请人：——

  公开号：US6153627A

  公开（公告）日：2000-11-28