8-chloro-11-(1-(cyclohexylmethyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并环庚烷吡啶
• 英文名称: 8-chloro-11-(1-(cyclohexylmethyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine
• 英文别名: VUF16138；13-Chloro-2-[1-(cyclohexylmethyl)piperidin-4-ylidene]-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene；13-chloro-2-[1-(cyclohexylmethyl)piperidin-4-ylidene]-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene
• 化学式: C₂₆H₃₁ClN₂
• 分子量: 406.999
• InChiKey: PEPNEROFUKNVQJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  29
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  16.1
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  地氯雷他定 、 环己烷基甲醛 在 三乙酰氧基硼氢化钠 作用下， 以 1,2-二氯乙烷 为溶剂， 以63%的产率得到8-chloro-11-(1-(cyclohexylmethyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine
  参考文献：
  名称：

  Route to Prolonged Residence Time at the Histamine H₁ Receptor: Growing from Desloratadine to Rupatadine

  摘要：

  Drug-target binding kinetics are an important predictor of in vivo drug efficacy, yet the relationship between ligand structures and their binding kinetics is often poorly understood. We show that both rupatadine (1) and desloratadine (2) have a long residence time at the histamine H-1 receptor (H1R). Through development of a [H-3]levocetirizine radiolabel, we find that the residence time of 1 exceeds that of 2 more than 10-fold. This was further explored with 22 synthesized rupatadine and desloratadine analogues. Methylene-linked cycloaliphatic or beta-branched substitutions of desloratadine increase the residence time at the H1R, conveying a longer duration of receptor antagonism. However, cycloaliphatic substituents directly attached to the piperidine amine (i.e., lacking the spacer) have decreased binding affinity and residence time compared to their methylene-linked structural analogues. Guided by docking studies, steric constraints within the binding pocket are hypothesized to explain the observed differences in affinity and binding kinetics between analogues.

  DOI：

  10.1021/acs.jmedchem.9b00447

文献信息

• [EN] TRICYCLIC COMPOUND AND PHARMACEUTICAL USE THEREOF<br/>[FR] COMPOSÉ TRICYCLIQUE ET SON UTILISATION PHARMACEUTIQUE<br/>[KO] 삼환식 화합물 및 이의 약학적 용도
  申请人：JD BIOSCIENCE INC

  公开号：WO2021086133A1

  公开（公告）日：2021-05-06

  본 발명의 화학식 1로 표시되는 삼환식 유도체 또는 이의 약학적으로 허용가능한 염인 화합물은 세로토닌 활성을 저해하는 효과가 우수하므로, 이를 포함하는 약학적 조성물은 세로토닌 활성화와 관련된 대사성 질환 등의 예방 또는 치료에 유용하게 사용될 수 있다.
• Route to Prolonged Residence Time at the Histamine H₁ Receptor: Growing from Desloratadine to Rupatadine
  作者：Reggie Bosma、Zhiyong Wang、Albert J. Kooistra、Nick Bushby、Sebastiaan Kuhne、Jelle van den Bor、Michael J. Waring、Chris de Graaf、Iwan J. de Esch、Henry F. Vischer、Robert J. Sheppard、Maikel Wijtmans、Rob Leurs

  DOI：10.1021/acs.jmedchem.9b00447

  日期：2019.7.25

  Drug-target binding kinetics are an important predictor of in vivo drug efficacy, yet the relationship between ligand structures and their binding kinetics is often poorly understood. We show that both rupatadine (1) and desloratadine (2) have a long residence time at the histamine H-1 receptor (H1R). Through development of a [H-3]levocetirizine radiolabel, we find that the residence time of 1 exceeds that of 2 more than 10-fold. This was further explored with 22 synthesized rupatadine and desloratadine analogues. Methylene-linked cycloaliphatic or beta-branched substitutions of desloratadine increase the residence time at the H1R, conveying a longer duration of receptor antagonism. However, cycloaliphatic substituents directly attached to the piperidine amine (i.e., lacking the spacer) have decreased binding affinity and residence time compared to their methylene-linked structural analogues. Guided by docking studies, steric constraints within the binding pocket are hypothesized to explain the observed differences in affinity and binding kinetics between analogues.