(6S,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-((R)-1-benzylpyrrolidin-3-yl)-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione | 1018814-78-2

• 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: (6S,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-((R)-1-benzylpyrrolidin-3-yl)-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione
• 英文别名: (6S,12aR)-6-benzo[1,3]dioxol-5-yl-2-[(R)-1-benzylpyrrolidin-3-yl]-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione；(6S,12aR)-6-(1,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-[(3R)-1-(phenylmethyl)-3-pyrrolidinyl]pyrazino[1a(2),2a(2):1,6]pyrido[3,4-b]indole-1,4-dione；(2S,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3R)-1-benzylpyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione
• CAS: 1018814-78-2
• 化学式: C₃₂H₃₀N₄O₄
• 分子量: 534.615
• InChiKey: PPJODYFRWIXBIM-VFXDQDQSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  40
• 可旋转键数：
  4
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  78.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (6S,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-((R)-1-benzylpyrrolidin-3-yl)-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione 在 palladium hydroxide on carbon 氢气 作用下， 以 乙酸乙酯 为溶剂， 反应 48.0h， 生成 (6S,12aR)-6-Benzo[1,3]dioxol-5-yl-2-(R)-pyrrolidin-3-yl-2,3,6,7,12,12a-hexahydro-pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
  参考文献：
  名称：

  CHIRAL TETRA-HYDRO BETA-CARBOLINE DERIVATIVES AND APPLICATIONS THEREOF AS ANTIPARASITIC COMPOUNDS

  摘要：

  该发明涉及使用手性四氢β-咔啉衍生物的化学式(I)来制备用于预防和/或治疗涉及具有磷酸二酯酶活性的寄生虫引起的寄生虫疾病的药物组合物，或其药用盐，其中：- R1和R2，相同或不同，代表氢原子或氟原子；- k为0或1的整数；- R3从以下群组中选择：■ 可选择取代的苯环■ 可选择取代的3'-N-吡啶环- R4是从以下群组中选择的一个基团：-NH-A-R5，-NHC(O)-R5和下面的化学式(II-a)到(II-c)的基团：该发明还涉及一些新的手性四氢β-咔啉衍生物。

  公开号：

  EP1914235A1
• 作为产物：
  描述：

  D-色氨酸甲酯 在 三乙胺 、 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 、 氯仿 为溶剂， 生成 (6S,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-((R)-1-benzylpyrrolidin-3-yl)-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione
  参考文献：
  名称：

  Drug to Genome to Drug: Discovery of New Antiplasmodial Compounds

  摘要：

  The dominant strategy for discovery of new antimalarial drugs relies on cell-free assays on specific biochemical pathways of Plasmodium falciparum . However, it appears that screening directly on the parasite is a more rewarding approach. The "drug to genome to drug" approach consists of testing a small set of structural analogues of a drug acting on human proteins that have plasmodial orthologues. Both man and plasmodium possess cyclic nucleotide phosphodiesterases (PDEs) that are key players of cell homeostasis. We synthesized and tested 40 analogues of tadalafil, a human PDE5 inhibitor, on P. falciparum in culture and obtained potent inhibitors of parasite growth. We discuss the structure-activity relationships, which support the hypothesis that our compounds kill the parasite via inhibition of plasmodial PDE activity. We also prove that antiplasmodial derivatives inhibit the hydrolysis of cyclic nucleotides of the parasite, validating the cAMP/cGMP pathways as therapeutic targets against Plasmodium falciparum .

  DOI：

  10.1021/jm1014617

文献信息

• Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer’s Disease
  作者：Fei Mao、Huan Wang、Wei Ni、Xinyu Zheng、Manjiong Wang、Keting Bao、Dazheng Ling、Xiaokang Li、Yixiang Xu、Haiyan Zhang、Jian Li

  DOI：10.1021/acschemneuro.7b00345

  日期：2018.2.21

  drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer’s disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier

  通过重新利用和重新开发现有药物的药物发现策略，合理地设计，合成和评估了一系列新型他达拉非衍生物，以寻找双靶点AChE / PDE5抑制剂作为阿尔茨海默氏病（AD）的良好候选药物。在这些衍生物中，1p和1w表现出优异的选择性双靶AChE / PDE5抑制活性和改善的血脑屏障（BBB）渗透性。重要的是1w·Cit（柠檬酸盐为1w）可以逆转东pol碱诱导的AD小鼠的认知功能障碍，并在增强体内cAMP反应元件结合蛋白（CREB）磷酸化方面表现出优异的作用，这是记忆形成和突触可塑性的关键因素。此外，与hAChE和hPDE5A的1w分子对接模拟证实了我们的设计策略是合理的。总而言之，我们的研究提供了一种潜在的选择性双靶AChE / PDE5抑制剂，作为治疗AD的良好候选药物，它也可以被视为小分子探针，以验证体内新颖的AD治疗方法。
• [EN] CHIRAL TETRA-HYDRO BETA-CARBOLINE DERIVATIVES, APPLICATIONS THEREOF AS ANTIPARASITIC COMPOUNDS<br/>[FR] DÉRIVÉS CHIRAUX DE TÉTRA-HYDRO BÉTA-CARBOLINE, LEURS APPLICATIONS EN TANT QUE COMPOSÉS ANTIPARASITAIRES
  申请人：UNIV LILLE 2 UNIVERSITE DU DRO

  公开号：WO2008044144A2

  公开（公告）日：2008-04-17

  [EN] The Invention relates to the use of chiral tetra-hydro beta carboline derivatives for the preparation of a pharmaceutical composition for the prevention and/or the treatment of parasitic diseases involving parasites having a phosphodiesterase activity. The invention also relates to some new chiral tetra-hydro beta-carboline derivatives.
  [FR] L'invention concerne des dérivés de tétra-hydro béta carboline utilisés pour la préparation d'une composition pharmaceutique destinée à la prévention et/ou au traitement de maladies parasitaires impliquant des parasites ayant une activité phosphodiestérase. L'invention concerne également certains dérivés chiraux de tétra-hydro béta-carboline.
• Drug to Genome to Drug: Discovery of New Antiplasmodial Compounds
  作者：Terence B. Beghyn、Julie Charton、Florence Leroux、Guillaume Laconde、Arnaud Bourin、Paul Cos、Louis Maes、Benoit Deprez

  DOI：10.1021/jm1014617

  日期：2011.5.12

  The dominant strategy for discovery of new antimalarial drugs relies on cell-free assays on specific biochemical pathways of Plasmodium falciparum . However, it appears that screening directly on the parasite is a more rewarding approach. The "drug to genome to drug" approach consists of testing a small set of structural analogues of a drug acting on human proteins that have plasmodial orthologues. Both man and plasmodium possess cyclic nucleotide phosphodiesterases (PDEs) that are key players of cell homeostasis. We synthesized and tested 40 analogues of tadalafil, a human PDE5 inhibitor, on P. falciparum in culture and obtained potent inhibitors of parasite growth. We discuss the structure-activity relationships, which support the hypothesis that our compounds kill the parasite via inhibition of plasmodial PDE activity. We also prove that antiplasmodial derivatives inhibit the hydrolysis of cyclic nucleotides of the parasite, validating the cAMP/cGMP pathways as therapeutic targets against Plasmodium falciparum .
• CHIRAL TETRA-HYDRO BETA-CARBOLINE DERIVATIVES AND APPLICATIONS THEREOF AS ANTIPARASITIC COMPOUNDS
  申请人：Université de Lille 2 Droit et Santé

  公开号：EP1914235A1

  公开（公告）日：2008-04-23

  The invention relates to the use of chiral tetra-hydro β-carboline derivatives of formula (I) for the preparation of pharmaceutical composition for the prevention and/or the treatment of parasitic diseases involving parasites having a phosphodiesterase activity: or a pharmaceutically acceptable salt thereof, in which: - R1 and R2, identical or different, represent a hydrogen atom or a fluorine atom; - k is an integer equal to 0 or 1; - R3 is selected from the group consisting of: ■ a phenyl ring optionally substituted ■ a 3'-N-pyridine ring optionally substituted - R4 is a group selected in the group consisting of the following groups: -NH-A-R5, -NHC(O)-R5 and the groups of formulas (II-a) to (II-c) below: The invention also relates to some new chiral tetra-hydro β-carboline derivatives.

  该发明涉及使用手性四氢β-咔啉衍生物的化学式(I)来制备用于预防和/或治疗涉及具有磷酸二酯酶活性的寄生虫引起的寄生虫疾病的药物组合物，或其药用盐，其中：- R1和R2，相同或不同，代表氢原子或氟原子；- k为0或1的整数；- R3从以下群组中选择：■ 可选择取代的苯环■ 可选择取代的3'-N-吡啶环- R4是从以下群组中选择的一个基团：-NH-A-R5，-NHC(O)-R5和下面的化学式(II-a)到(II-c)的基团：该发明还涉及一些新的手性四氢β-咔啉衍生物。