(R)-N-tert-butyl-3-[(2S,3S)-3-(2,6-dimethylphenoxyacetyl)amino-2-glutaryloxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide | 343330-25-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (R)-N-tert-butyl-3-[(2S,3S)-3-(2,6-dimethylphenoxyacetyl)amino-2-glutaryloxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide
• 英文别名: 5-[(2S,3S)-1-[(4R)-4-(tert-butylcarbamoyl)-5,5-dimethyl-1,3-thiazolidin-3-yl]-3-[[2-(2,6-dimethylphenoxy)acetyl]amino]-1-oxo-4-phenylbutan-2-yl]oxy-5-oxopentanoic acid
• CAS: 343330-25-6
• 化学式: C₃₅H₄₇N₃O₈S
• 分子量: 669.839
• InChiKey: FDDSVDLPHCADKM-LGXAAPQCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  47
• 可旋转键数：
  16
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.51
• 拓扑面积：
  177
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (R)-N-tert-butyl-3-[(2S,3S)-3-(2,6-dimethylphenoxyacetyl)amino-2-glutaryloxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 1-羟基苯并三唑 、 三乙胺 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 4-(Carboxymethyl-carbamoyl)-butyric acid (1S,2S)-1-((R)-4-tert-butylcarbamoyl-5,5-dimethyl-thiazolidine-3-carbonyl)-2-[2-(2,6-dimethyl-phenoxy)-acetylamino]-3-phenyl-propyl ester
  参考文献：
  名称：

  抗HIV双药的设计，合成和生物学评估。HIV蛋白酶抑制剂与逆转录酶抑制剂通过自发可裂解的连接物的结合物。

  摘要：

  基于前药概念以及两种不同类型的抗HIV药物的组合，我们设计并合成了一系列抗HIV双重药物，其中包括与核苷逆转录酶抑制剂结合的HIV蛋白酶抑制剂，以增强抗病毒活性。对于缀合，已经研究了连接两种不同类型抑制剂的一系列接头。如从能量上有利的环化到五元环所预期的，与使用戊二酰基氨基酸接头的化合物相比，使用琥珀酰氨基酸接头的双药物显示通过自发酰亚胺形成以更快的速率释放母体药物。在双重毒品中，与单个成分相比，带有谷氨酰甘氨酸接头的KNI-1039（3b）具有极强的抗HIV活性。双重药物3b在培养基中相对稳定，而在细胞匀浆中可再生活性物质。这些结果表明3b的抗HIV活性的协同增强可能是由于它们渗透入靶细胞的能力以及随后在细胞质中两种不同类型的抗HIV剂的再生。

  DOI：

  10.1016/s0968-0896(01)00045-1
• 作为产物：
  描述：

  戊二酸酐 、 KNI-727 在 二环己胺 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 以60%的产率得到(R)-N-tert-butyl-3-[(2S,3S)-3-(2,6-dimethylphenoxyacetyl)amino-2-glutaryloxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide
  参考文献：
  名称：

  抗HIV双药的设计，合成和生物学评估。HIV蛋白酶抑制剂与逆转录酶抑制剂通过自发可裂解的连接物的结合物。

  摘要：

  基于前药概念以及两种不同类型的抗HIV药物的组合，我们设计并合成了一系列抗HIV双重药物，其中包括与核苷逆转录酶抑制剂结合的HIV蛋白酶抑制剂，以增强抗病毒活性。对于缀合，已经研究了连接两种不同类型抑制剂的一系列接头。如从能量上有利的环化到五元环所预期的，与使用戊二酰基氨基酸接头的化合物相比，使用琥珀酰氨基酸接头的双药物显示通过自发酰亚胺形成以更快的速率释放母体药物。在双重毒品中，与单个成分相比，带有谷氨酰甘氨酸接头的KNI-1039（3b）具有极强的抗HIV活性。双重药物3b在培养基中相对稳定，而在细胞匀浆中可再生活性物质。这些结果表明3b的抗HIV活性的协同增强可能是由于它们渗透入靶细胞的能力以及随后在细胞质中两种不同类型的抗HIV剂的再生。

  DOI：

  10.1016/s0968-0896(01)00045-1

文献信息

• Development of Water-Soluble Prodrugs of the HIV-1 Protease Inhibitor KNI-727:  Importance of the Conversion Time for Higher Gastrointestinal Absorption of Prodrugs Based on Spontaneous Chemical Cleavage
  作者：Youhei Sohma、Yoshio Hayashi、Tomoko Ito、Hikaru Matsumoto、Tooru Kimura、Yoshiaki Kiso

  DOI：10.1021/jm030009m

  日期：2003.9.1

  We designed and synthesized a series of water-soluble prodrugs of the HIV-1 protease inhibitor KNI-727 (1), which is a sparingly water-soluble drug with a water solubility of 5.5 mug/mL. These prodrugs, which contain a water-soluble auxiliary with two tandem-linked units, i.e., a self-cleavable spacer and a solubilizing moiety with an ionized amino function, exhibited a marked increase in water solubility (>10(4)-fold) compared with the parent drug 1. The mechanism of conversion to the parent drug 1 is not enzymatic but through a chemical cleavage at the spacer via an intramolecular cyclization-elimination reaction through an imide formation under physiological conditions. To diversify the conversion time for the parent drug regeneration, chemical modification of the auxiliary was carried out focusing on the introduction of cyclic tertiary amines, which can modify the basicity and/or conformational flexibility of the terminal amino function at the solubilizing moiety, and the change in bond length, which can attenuate the five-membered ring intermediate formation in the cleavage. These newly synthesized water-soluble prodrugs exhibited a practical water solubility with values greater than 50 mg/mL and enabled the constant regeneration of the parent drug 1 with diversified conversion times ranging from 4 min to 34 h as t(1/2) values under physiological conditions. All the water-soluble prodrugs tested regenerated the parent drug 1 in vivo as well as in vitro. A clear increase in the gastrointestinal absorption was observed in prodrugs 8, 12, and 13 with bioavailability (BA) values of 23%, 26%, and 29%, respectively. These BA values were 1.5-1.9-fold higher than that in the administration of the parent drug 1 alone. Other prodrugs showed only a similar or decreased BA compared to the parent drug 1. From these results, we found that not only a high water solubility but also an appropriate conversion time of the prodrug with a relatively narrow limit of around 35 min via intraduodenal administration was necessary for significant improvement of the gastrointestinal absorption in water-soluble prodrugs based on the spontaneous chemical cleavage. This is the first successful water-soluble prodrug that suggests an increased BA value greater than the parent drug in HIV-1 protease inhibitors and is the first study to show the importance of optimal conversion time in water-soluble prodrugs. Consequently, a water-soluble strategy that can control the conversion time would be extensively applicable to improve the gastrointestinal absorption of sparingly water-soluble drugs. The present information is an intriguing discovery and is one of the key factors that will contribute to the future design of practical water-soluble prodrugs.
• ‘Double-drugs’— A new class of prodrug form of an HIV protease inhibitor conjugated with a reverse transcriptase inhibitor by a spontaneously cleavable linker
  作者：Hikaru Matsumoto、Tomonori Hamawaki、Hisashi Ota、Tooru Kimura、Toshiyuki Goto、Kouichi Sano、Yoshio Hayashi、Yoshiaki Kiso

  DOI：10.1016/s0960-894x(00)00202-x

  日期：2000.6

  We designed and synthesized a new series of prodrug-type anti-HIV agents consisting of a peptidomimetic HIV protease inhibitor conjugated with a nucleoside reverse transcriptase inhibitor in an effort to enhance the antiviral activity. For the conjugation, a series of linkers that conjoin the two different classes of inhibitors have been investigated. Conjugates using a succinyl amino acid linker were shown to release the parent components via the spontaneous imide formation at a faster rate compared to conjugates using a glutaryl amino acid linker, as expected from the energetically favorable cyclization to the five-membered ring. Herein, we report a new 'double-drug' 4b (KNI-1039) with a glutarylglycine linker, which exhibited extremely potent anti-HIV activity compared with that of the individual components. (C) 2000 Elsevier Science Ltd. All rights reserved.
• Controlled drug release
  作者：Hikaru Matsumoto、Youhei Sohma、Tooru Kimura、Yoshio Hayashi、Yoshiaki Kiso

  DOI：10.1016/s0960-894x(01)00007-5

  日期：2001.2

  We designed and synthesized a series of highly water-soluble prodrugs of an HIV protease inhibitor, KNI-727 (1), containing tandem-linked two auxiliary units, a solubilizing moiety and a self-cleavable spacer. Prodrugs with an ionized amino group at the solubilizing moiety exhibited a remarkable increase of water-solubility (>10(4) fold) compared to the parent drug 1. These prodrugs released 1 not enzymatically, but chemically via an intramolecular cyclization-elimination reaction through an imide formation in physiological conditions. Diversified rates of parent drug release were observed when the chemical structure of both the solubilizing and the spacer moieties were modified. This new approach for water-soluble prodrugs will enable to control chemically the release of parent drug as well as to maintain high water-solubility. (C) 2001 Elsevier Science Ltd. All rights reserved.