XK234 | 153223-21-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂卓
• 英文名称: XK234
• 英文别名: 2H-1,3-Diazepin-2-one, 1,3-bis(cyclopropylmethyl)hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-, (4R,5S,6S,7R)-；(4R,5S,6S,7R)-4,7-dibenzyl-1,3-bis(cyclopropylmethyl)-5,6-dihydroxy-1,3-diazepan-2-one
• CAS: 153223-21-3
• 化学式: C₂₇H₃₄N₂O₃
• 分子量: 434.579
• InChiKey: YMTOUOZOBVYCFQ-XPGKHFPBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  64
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  XK234 在 盐酸 、 sodium hydroxide 、 二乙胺基三氟化硫 、 N,N-二异丙基乙胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 30.83h， 生成 (4S,5S,6R)-tetrahydro-1,3-bis--5-hydroxy-4-(1S-fluoro-2-phenylethyl)-6-(phenylmethyl)-2(1H)-pyrimidinone
  参考文献：
  名称：

  Stereospecific, Stereoselective Rearrangement of Hexahydro-1,3-diazepin-2-ones to Tetrahydropyrimidin-2-ones and Imidazolidin-2-ones, a Useful Route for the Synthesis of HIV Protease Inhibitors

  摘要：

  We have discovered that hexahydro-5,6-dihydroxy-1,3-diazepin-2-ones can undergo a stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding tetrahydro-5-hydroxypyrimidin-2-ones. This reaction is very general and proceeds in excellent yields. The rearrangement proceeds through the formation of the aziridinium cationic intermediate I, which is subsequently opened by nucleophilic attack (S(N)2) at the less hindered carbon to give the rearranged product. The X-ray structure determination of the rearranged product (17a; Figure 1) confirmed the structure and the stereochemical assignments and is consistent with:the proposed mechanism. When the urea nitrogens are not substituted, the aziridine product can be isolated, and its structure (24; Figure 2) was also confirmed by X-ray analysis. The aziridine product can be used as a mono N-protecting group to synthesize differentially disubstituted N,N'-dialkylated tetrahydropyrimidin-2-one analogues. The tetrahydro-5-hydroxypyrimidin-2-ones can further undergo a second stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding imidazolidinones. This second rearrangement is also very general and proceeds in good yields. These tetrahydro-5-hydroxypyrimidin-2-ones and imidazolidinones have previously been shown to be potent HIVPR inhibitors.

  DOI：

  10.1021/jo980533e
• 作为产物：
  描述：

  (4R,5S,6S,7R)-hexahydro-5,6-bis[2-(trimethylsilyl)ethoxymethoxy]-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one 在 盐酸 、 sodium hydride 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 2.5h， 生成 XK234
  参考文献：
  名称：

  环状HIV蛋白酶抑制剂：合成，构象分析，P2 / P2'的结构活性关系和环状脲的分子识别。

  摘要：

  HIV-1蛋白酶（HIV-1PR）与拟肽抑制剂的复合物的高分辨率X射线结构揭示了结构水分子的存在，该结构水分子氢键合到酶的可移动侧翼和过渡过渡带两侧的两个羰基上态的抑制剂。利用C2对称二醇抑制剂的结构活性关系，计算机辅助药物设计工具和第一原理，我们设计并合成了新型的环状脲，其结合了该结构水并将侧链残基预先组织为最佳结合构象。构象分析表明对伪双轴苄基和伪二季基羟基取代基的偏爱和对RSSR立体化学的对映体偏爱。HIV-1PR和一种环状尿素DMP323的配合物的X射线和溶液NMR结构证实了结构水的置换。另外，结合的和“未结合的”（小分子X射线）配体具有相似的构象。提出了高度的预组织，互补性和水置换的熵增益，以解释这些小分子对酶的高度亲和力。小尺寸可能有助于在动物中观察到良好的口服生物利用度。基于结构优化的侧链填充酶的S2和S2'口袋产生了DMP323，该药物已在I期临床试验中进行了研究，但发现其

  DOI：

  10.1021/jm9602571

文献信息

• Stereoisomers of Cyclic Urea HIV-1 Protease Inhibitors:  Synthesis and Binding Affinities
  作者：Robert F. Kaltenbach、David A. Nugiel、Patrick Y. S. Lam、Ronald M. Klabe、Steven P. Seitz

  DOI：10.1021/jm980255b

  日期：1998.12.1

  We have synthesized stereoisomers of cyclic urea HIV-1 protease inhibitors to study the effect of varying configurations on binding affinities. Four different synthetic approaches were used to prepare the desired cyclic urea stereoisomers. The original cyclic urea synthesis using amino acid starting materials was used to prepare three isomers. Three additional isomers were prepared by synthetic routes

  我们已经合成了环状脲HIV-1蛋白酶抑制剂的立体异构体，以研究各种构型对结合亲和力的影响。使用四种不同的合成方法来制备所需的环状脲立体异构体。使用氨基酸起始原料的原始环状脲合成用于制备三种异构体。通过使用L-酒石酸和D-山梨糖醇作为手性原料的合成路线制备了三种另外的异构体。环状脲反式二醇的立体选择性羟基转化用于制备三种另外的异构体。共准备了10种可能的全部9种环状脲立体异构体，并描述了它们的结合亲和力。
• Calculated and Experimental Low-Energy Conformations of Cyclic Urea HIV Protease Inhibitors
  作者：C. Nicholas Hodge、Patrick Y. S. Lam、Charles J. Eyermann、Prabhakar K. Jadhav、Y. Ru、Christina H. Fernandez、George V. De Lucca、Chong-Hwan Chang、Robert F. Kaltenbach、Edward R. Holler、Francis Woerner、Wayne F. Daneker、George Emmett、Joseph C. Calabrese、Paul E. Aldrich

  DOI：10.1021/ja972357h

  日期：1998.5.1

  limited number of studies of complex organics that compare calculated and experimentally observed conformations. To assess our ability to predict a priori favored conformations of cyclic HIV protease (HIV-1 PR) inhibitors, conformational minima for nine 4,7-bis(phen...

  影响柔性配体对受体亲和力的一个重要因素是获得结合构象所需的内部应变能。对于大多数生物学感兴趣的系统，计算完全平衡的结合和游离配体和受体构象的集合在计算上是不可能的；因此，将新结构作为给定受体的潜在高亲和力配体的定性评估可以受益于考虑配体的结合和未结合（通常是水性）低能几何形状以及它们的内能差异。尽管可以使用许多计算生成和评估小分子构象偏好的技术，比较计算和实验观察到的构象的复杂有机物研究数量有限。为了评估我们预测循环 HIV 蛋白酶 (HIV-1 PR) 抑制剂的先验偏好构象的能力，九个 4,7-bis(phen...
• Design, Synthesis, and Evaluation of Tetrahydropyrimidinones as an Example of a General Approach to Nonpeptide HIV Protease Inhibitors
  作者：George V. De Lucca、Jing Liang、Paul E. Aldrich、Joe Calabrese、Beverly Cordova、Ronald M. Klabe、Marlene M. Rayner、Chong-Hwan Chang

  DOI：10.1021/jm970081i

  日期：1997.5.1

  Re-examination of the design of the cyclic urea class of HIV protease (HIVPR) inhibitors suggests a general approach to designing novel nonpeptide cyclic HIVPR inhibitors. This process involves the inversion of the stereochemical centers of the core transition-state isostere of the linear HIVPR inhibitors and cyclization of the resulting core using an appropriate cyclizing reagent. As an example, this

  对HIV蛋白酶（HIVPR）抑制剂的环状脲类设计的重新审查提出了设计新型非肽环状HIVPR抑制剂的一般方法。该过程涉及线性HIVPR抑制剂的核心过渡态等位体的立体化学中心的反转，以及使用合适的环化试剂环化所得核心。例如，该方法应用于HIVPR抑制剂的二氨基醇类，得到四氢嘧啶酮。四氢嘧啶酮的构象分析及其与HIVPR活性位点相互作用的模型表明，修饰导致了非常有效的HIVPR抑制剂（24种，Ki = 0.018 nM）。具有HIVPR的24配合物的X射线晶体学结构证实了分析和模型预测。
• Preparation and Structure−Activity Relationship of Novel P1/P1‘-Substituted Cyclic Urea-Based Human Immunodeficiency Virus Type-1 Protease Inhibitors
  作者：David A. Nugiel、Kim Jacobs、Tabitha Worley、Mona Patel、Robert F. Kaltenbach、Dayton T. Meyer、Prabhakar K. Jadhav、George V. De Lucca、Thomas E. Smyser、Ronald M. Klabe、Lee T. Bacheler、Marlene M. Rayner、Steven P. Seitz

  DOI：10.1021/jm960083n

  日期：1996.1.1

  A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.
• Stereospecific Synthesis, Structure−Activity Relationship, and Oral Bioavailability of Tetrahydropyrimidin-2-one HIV Protease Inhibitors
  作者：George V. De Lucca、Jing Liang、Indawati De Lucca

  DOI：10.1021/jm9803626

  日期：1999.1.1

  The use of tetrahydropyrimidinones as an alternate scaffold for designing HIVPR inhibitors has advantages, over the previously disclosed hexahydro-1,3-diazepin-2-ones, of being more unsymmetrical (different P1/P1'), less crystalline, more soluble, and more lipophilic (mono-ol vs diol). They show a better translation of K-i to IC90 for the more polar P2 groups that in general give the more potent enzyme inhibitors. Structure-activity relationship (SAR) studies of the tetrahydropyrimidinones showed that the phenylethyl P1' substituent, the hydroxyl group, and the urea carbonyl are all critical for good activity. However, there was significant flexibility in the possible P2/P2' substituents that could be used. Many analogues that contained identical or different P2/P2' substituents, or only one P2 substituent, were found to have excellent enzyme potency and several had excellent antiviral potency. Several of these compounds were examined for oral bioavailability in the rat or the dog at 10 mg/kg. However, the oral bioavailability of the tetrahydropyrimidinones was, in general, less than the corresponding hexahydro-1,3-diazepin-2-ones. Unfortunately, when all factors are considered, including potency, protein binding, solubility, bioavailability, and resistance profile, the tetrahydropyrimidinones did not offer any advantage over the previously disclosed hexahydro-1,3-diazepin-2-ones series.