4-((5-amino-6-chloropyrimidin-4-yl)amino)benzamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-((5-amino-6-chloropyrimidin-4-yl)amino)benzamide
• 英文别名: 4-[(5-Amino-6-chloropyrimidin-4-yl)amino]benzamide；4-[(5-amino-6-chloropyrimidin-4-yl)amino]benzamide
• 化学式: C₁₁H₁₀ClN₅O
• 分子量: 263.686
• InChiKey: XNOBLVMSSWYHDQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  107
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-((5-amino-6-chloropyrimidin-4-yl)amino)benzamide 在 乙基磺酸 、 palladium on activated charcoal 、 氢气 作用下， 以 甲醇 为溶剂， 生成 4-(9H-purin-9-yl)benzamide
  参考文献：
  名称：

  Targeting different binding sites in the CFTR structures allows to synergistically potentiate channel activity

  摘要：

  Recent evidence shows that combination of correctors and potentiators, such as the drug ivacaftor (VX-770), can significantly restore the functional expression of mutated Cystic Fibrosis Transmembrane conductance Regulator (CFTR), an anion channel which is mutated in cystic fibrosis (CF). The success of these combinatorial therapies highlights the necessity of identifying a broad panel of specific binding mode modulators, occupying several distinct binding sites at structural level. Here, we identified two small molecules, SBC040 and SBC219, which are two efficient cAMP-independent potentiators, acting at low concentration of forskolin with EC50 close to 1 mu M and in a synergic way with the drug VX-770 on several CFTR mutants of classes II and III. Molecular dynamics simulations suggested potential SBC binding sites at the vicinity of ATP-binding sites, distinct from those currently proposed for VX-770, outlining SBC molecules as members of a new family of potentiators. (C) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112116
• 作为产物：
  描述：

  4,6-二氯-5-氨基嘧啶 、 对氨基苯甲酰胺 在 盐酸 作用下， 以 水 、 正丁醇 为溶剂， 反应 15.0h， 生成 4-((5-amino-6-chloropyrimidin-4-yl)amino)benzamide
  参考文献：
  名称：

  功能化的6-（哌啶-1-基）-8,9-二苯基嘌呤作为CB1受体的反向激动剂-SAR致力于选择性和外围化。

  摘要：

  1型大麻素受体（CB1）的拮抗剂可用于治疗糖尿病，肝病和纤维化。Otenabant（1）是一种有效且选择性的CB1反向激动剂，目前正在研究中作为抗肥胖药，但一旦已知与另一种市售反向激动剂rimonabant（2）相关的不良反应，其发展就会中止。CB1的非组织选择性拮抗剂具有高水平的脑部渗透性，会对一小部分患者产生不良影响，包括焦虑，抑郁和自杀意念。当前，正在努力生产大脑渗透受限的化合物。在本报告中，探索了新型的1类似物，以开发和测试外围化策略。研究了1的哌啶作为连接基，它被烷基，杂烷基，使用胺，酰胺，磺酰胺，磺酰胺，氨基甲酸酯，肟，am或胍形式的连接基形成芳基和杂芳基。我们还报告了嘌呤核9位中4-氯苯基的更多极性替代物，这改善了分子的计算物理性能。这些研究产生了诸如hCB1的有效反向激动剂之类的化合物，例如75，对hCB1的选择性比hCB2高。SAR研究揭示了调节物理特性以限制大脑暴露的方

  DOI：

  10.1016/j.bmc.2019.07.002

文献信息

• Functionalized 6-(piperidin-1-yl)-8,9-diphenyl purines as inverse agonists of the CB1 receptor – SAR efforts towards selectivity and peripheralization
  作者：George Amato、Robert Wiethe、Amruta Manke、Vineetha Vasukuttan、Rodney Snyder、Scott Runyon、Rangan Maitra

  DOI：10.1016/j.bmc.2019.07.002

  日期：2019.8

  is functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a connector in the form of an amine, amide, sulfonamide, sulfamide, carbamate, oxime, amidine, or guanidine. We also report more polar replacements for the 4-chlorophenyl group in the 9-position of the purine core, which improve calculated physical properties of the molecules. These studies resulted in compounds such as 75 that

  1型大麻素受体（CB1）的拮抗剂可用于治疗糖尿病，肝病和纤维化。Otenabant（1）是一种有效且选择性的CB1反向激动剂，目前正在研究中作为抗肥胖药，但一旦已知与另一种市售反向激动剂rimonabant（2）相关的不良反应，其发展就会中止。CB1的非组织选择性拮抗剂具有高水平的脑部渗透性，会对一小部分患者产生不良影响，包括焦虑，抑郁和自杀意念。当前，正在努力生产大脑渗透受限的化合物。在本报告中，探索了新型的1类似物，以开发和测试外围化策略。研究了1的哌啶作为连接基，它被烷基，杂烷基，使用胺，酰胺，磺酰胺，磺酰胺，氨基甲酸酯，肟，am或胍形式的连接基形成芳基和杂芳基。我们还报告了嘌呤核9位中4-氯苯基的更多极性替代物，这改善了分子的计算物理性能。这些研究产生了诸如hCB1的有效反向激动剂之类的化合物，例如75，对hCB1的选择性比hCB2高。SAR研究揭示了调节物理特性以限制大脑暴露的方
• Compounds for treating cystic fibrosis
  申请人：CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS)

  公开号：US10414768B2

  公开（公告）日：2019-09-17

  The present invention relates to compounds of Formula (I) or pharmaceutically acceptable enantiomers, salts, solvates or prodrugs thereof. The invention further relates to the use of the compounds of Formula (I) for the treatment of cystic fibrosis. The invention also relates to a process for manufacturing compounds of Formula (I).

  本发明涉及式（I）化合物或其药学上可接受的对映体、盐、溶液剂或原药。本发明还涉及式（I）化合物用于治疗囊性纤维化的用途。本发明还涉及一种制造式（I）化合物的工艺。
• [EN] COMPOUNDS FOR TREATING CYSTIC FIBROSIS<br/>[FR] COMPOSÉS POUR LE TRAITEMENT DE LA FIBROSE KYSTIQUE
  申请人：CENTRE NAT DE LA RECH SCIENT (CNRS)

  公开号：WO2016087665A3

  公开（公告）日：2016-09-09
• COMPOUNDS FOR TREATING CYSTIC FIBROSIS
  申请人：Centre National de la Recherche Scientifique (CNRS)

  公开号：EP3226861A2

  公开（公告）日：2017-10-11
• Targeting different binding sites in the CFTR structures allows to synergistically potentiate channel activity
  作者：Lionel Froux、Ahmad Elbahnsi、Benjamin Boucherle、Arnaud Billet、Nesrine Baatallah、Brice Hoffmann、Julien Alliot、Renaud Zelli、Wael Zeinyeh、Romain Haudecoeur、Benoit Chevalier、Antoine Fortuné、Sandra Mirval、Christophe Simard、Pierre Lehn、Jean-Paul Mornon、Alexandre Hinzpeter、Frédéric Becq、Isabelle Callebaut、Jean-Luc Décout

  DOI：10.1016/j.ejmech.2020.112116

  日期：2020.3

  Recent evidence shows that combination of correctors and potentiators, such as the drug ivacaftor (VX-770), can significantly restore the functional expression of mutated Cystic Fibrosis Transmembrane conductance Regulator (CFTR), an anion channel which is mutated in cystic fibrosis (CF). The success of these combinatorial therapies highlights the necessity of identifying a broad panel of specific binding mode modulators, occupying several distinct binding sites at structural level. Here, we identified two small molecules, SBC040 and SBC219, which are two efficient cAMP-independent potentiators, acting at low concentration of forskolin with EC50 close to 1 mu M and in a synergic way with the drug VX-770 on several CFTR mutants of classes II and III. Molecular dynamics simulations suggested potential SBC binding sites at the vicinity of ATP-binding sites, distinct from those currently proposed for VX-770, outlining SBC molecules as members of a new family of potentiators. (C) 2020 Elsevier Masson SAS. All rights reserved.