(4-{4-[2-(17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-11,28-dioxa-4-aza-tricyclo[22.3.1.0^4,9]octacos-18-en-12-yl)propenyl]-2-methoxy-cyclohexyloxycarbonylamino}phenyl)acetic acid

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯内酰胺
• 英文名称: (4-{4-[2-(17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-11,28-dioxa-4-aza-tricyclo[22.3.1.0^4,9]octacos-18-en-12-yl)propenyl]-2-methoxy-cyclohexyloxycarbonylamino}phenyl)acetic acid
• 英文别名: 2-[4-[[(1R,2R,4R)-4-[(E)-2-[(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-17-prop-2-enyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-en-12-yl]prop-1-enyl]-2-methoxycyclohexyl]oxycarbonylamino]phenyl]acetic acid
• 化学式: C₅₃H₇₆N₂O₁₅
• 分子量: 981.191
• InChiKey: ZLJNMBLYGARGIL-WWBHIXRUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  70
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.66
• 拓扑面积：
  234
• 氢给体数：
  4
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  三光气 、 他克莫司 、 (4-aminophenyl)acetic acid trimethylsilyl ester 在 4-二甲氨基吡啶 、 盐酸 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 (4-{4-[2-(17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-11,28-dioxa-4-aza-tricyclo[22.3.1.0^4,9]octacos-18-en-12-yl)propenyl]-2-methoxy-cyclohexyloxycarbonylamino}phenyl)acetic acid
  参考文献：
  名称：

  A Locally Active Antiinflammatory Macrolide (MLD987) for Inhalation Therapy of Asthma

  摘要：

  One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC50 values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED50 = 1 mg/kg) or by inhalation (ED50 = 0.4 mg/ kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, I had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the longterm therapy of asthma of all grades of severity.

  DOI：

  10.1021/jm031101l

文献信息

• A Locally Active Antiinflammatory Macrolide (MLD987) for Inhalation Therapy of Asthma
  作者：Rene Hersperger、Karl-Heinz Buchheit、Salvatore Cammisuli、Albert Enz、Olivier Lohse、Monique Ponelle、Walter Schuler、Alain Schweitzer、Christoph Walker、Hartmut Zehender、Gerhard Zenke、Alfred G. Zimmerlin、Markus Zollinger、Lazzaro Mazzoni、John R. Fozard

  DOI：10.1021/jm031101l

  日期：2004.9.1

  One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC50 values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED50 = 1 mg/kg) or by inhalation (ED50 = 0.4 mg/ kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, I had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the longterm therapy of asthma of all grades of severity.