morpholinocarbonylhexahydro-L-phenylalanine | 119601-26-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: morpholinocarbonylhexahydro-L-phenylalanine
• 英文别名: (2S)-3-cyclohexyl-2-(morpholine-4-carbonylamino)propanoic acid
• CAS: 119601-26-2
• 化学式: C₁₄H₂₄N₂O₄
• 分子量: 284.356
• InChiKey: COWMZXVAPIXZHK-LBPRGKRZSA-N

物化性质

• 沸点：
  543.8±50.0 °C(predicted)
• 密度：
  1.189±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  78.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  morpholinocarbonylhexahydro-L-phenylalanine 在 盐酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 反应 19.0h， 生成
  参考文献：
  名称：

  Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study

  摘要：

  近年来，共价拟肽蛋白酶抑制剂在药物研发中备受关注。这些抑制剂通过被称为弹头的亲电基团与具有催化活性的氨基酸共价结合。共价抑制在药效学特性方面具有优势，但也可能因非选择性脱靶蛋白结合而产生毒性风险。因此，将活性弹头与合适的拟肽序列正确地结合在一起非常重要。本文研究了知名弹头与适合五种不同蛋白酶的拟肽序列相结合的选择性，强调了两个结构部分（弹头和拟肽序列）对亲和力和选择性的影响。分子对接深入了解了抑制剂在不同酶的结合口袋内的预测结合模式。此外，还通过核磁共振和液相色谱-质谱反应性测定以及量子力学模拟，研究了弹头与丝氨酸/苏氨酸和半胱氨酸亲核模型的反应性。

  DOI：

  10.3390/ijms24087226
• 作为产物：
  描述：

  L-环己基丙氨酸 在 甲醇 、 氯化亚砜 、 碳酸氢钠 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 35.0h， 生成 morpholinocarbonylhexahydro-L-phenylalanine
  参考文献：
  名称：

  Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study

  摘要：

  近年来，共价拟肽蛋白酶抑制剂在药物研发中备受关注。这些抑制剂通过被称为弹头的亲电基团与具有催化活性的氨基酸共价结合。共价抑制在药效学特性方面具有优势，但也可能因非选择性脱靶蛋白结合而产生毒性风险。因此，将活性弹头与合适的拟肽序列正确地结合在一起非常重要。本文研究了知名弹头与适合五种不同蛋白酶的拟肽序列相结合的选择性，强调了两个结构部分（弹头和拟肽序列）对亲和力和选择性的影响。分子对接深入了解了抑制剂在不同酶的结合口袋内的预测结合模式。此外，还通过核磁共振和液相色谱-质谱反应性测定以及量子力学模拟，研究了弹头与丝氨酸/苏氨酸和半胱氨酸亲核模型的反应性。

  DOI：

  10.3390/ijms24087226

文献信息

• Design and Synthesis of Dipeptide Nitriles as Reversible and Potent Cathepsin S Inhibitors
  作者：Yancey D. Ward、David S. Thomson、Leah L. Frye、Charles L. Cywin、Tina Morwick、Michel J. Emmanuel、Renée Zindell、Daniel McNeil、Younes Bekkali、Marc Girardot,、Matt Hrapchak、Molly DeTuri、Kathy Crane、Della White、Susan Pav、Yong Wang、Ming-Hong Hao、Christine A. Grygon、Mark E. Labadia、Dorothy M. Freeman、Walter Davidson、Jerry L. Hopkins、Maryanne L. Brown、Denice M. Spero

  DOI：10.1021/jm020209i

  日期：2002.12.1

  T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in

  免疫应答的特异性取决于外源蛋白的加工和抗原肽在细胞表面的呈递。从理论上讲，抑制抗原呈递以及随后激活T细胞应能调节免疫反应。半胱氨酸蛋白酶组织蛋白酶S在抗原呈递中执行基本步骤，因此代表了诱人的抑制靶标。本文中，我们报告了一系列基于二肽腈的有效且可逆的组织蛋白酶S抑制剂。这些抑制剂在人B细胞系中显示出对目标酶的纳摩尔抑制作用以及细胞效价。还报道了与组织蛋白酶S共结晶的可逆抑制剂的第一个X射线晶体结构。
• Subnanomolar Cathepsin S Inhibitors with High Selectivity: Optimizing Covalent Reversible α‐Fluorovinylsulfones and α‐Sulfonates as Potential Immunomodulators in Cancer
  作者：Natalie Fuchs、Mergim Meta、Bellinda Lantzberg、Matthias Bros、Seah Ling Kuan、Tanja Weil、Tanja Schirmeister

  DOI：10.1002/cmdc.202300160

  日期：2023.8

  The cysteine protease cathepsin S (CatS) is overexpressed in many tumors. It is known to be involved in tumor progression as well as antigen processing in antigen‐presenting cells (APC). Recent evidence suggests that silencing CatS improves the anti‐tumor immune response in several cancers. Therefore, CatS is an interesting target to modulate the immune response in these diseases. Here, we present a series of covalent‐reversible CatS inhibitors based on the α‐fluorovinylsulfone and ‐sulfonate warheads. We optimized two lead structures by molecular docking approaches, resulting in 22 final compounds which were evaluated in fluorometric enzyme assays for CatS inhibition and for selectivity towards the off‐targets CatB and CatL. The most potent inhibitor in the series has subnanomolar affinity (K_i=0.08 nM) and more than 100,000‐fold selectivity towards cathepsins B and L. These new reversible and non‐cytotoxic inhibitors could serve as interesting leads to develop new immunomodulators in cancer therapy.

  摘要半胱氨酸蛋白酶 cathepsin S（CatS）在许多肿瘤中过度表达。众所周知，它参与了肿瘤的进展以及抗原递呈细胞（APC）的抗原处理。最近的证据表明，沉默 CatS 可以改善几种癌症的抗肿瘤免疫反应。因此，CatS 是调节这些疾病免疫反应的一个有趣靶点。在此，我们介绍了一系列基于α-氟乙烯砜和-磺酸盐弹头的共价可逆 CatS 抑制剂。我们通过分子对接方法优化了两种先导结构，最终得到了 22 种化合物，并在荧光酶测定法中评估了它们对 CatS 的抑制作用以及对非靶标 CatB 和 CatL 的选择性。该系列中最有效的抑制剂具有亚摩尔亲和力（Ki=0.08 nM），对Cathepsins B和L的选择性超过100,000倍。
• Nor-statine and nor-cyclostatine polypeptides
  申请人：PFIZER INC.

  公开号：EP0266950A2

  公开（公告）日：1988-05-11

  Polypeptides and derivatives thereof containing nor-statine and nor-cyclostatine are useful for inhibiting the angiotensinogen-cleaving action of the enzyme renin.

  含有去甲司他汀和去甲环司他汀的多肽及其衍生物可用于抑制肾素酶的血管紧张素原分解作用。
• Novel compounds and compositions as protease inhibitors
  申请人：AXYS PHARMACEUTICALS, INC.

  公开号：EP1452522A2

  公开（公告）日：2004-09-01

  The present invention relates to novel N-cyanomethyl amides which are cysteine protease inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.

  本发明涉及作为半胱氨酸蛋白酶抑制剂的新型 N-氰甲基酰胺、其药学上可接受的盐和 N-氧化物、它们作为治疗剂的用途及其制造方法。
• Potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme identified in rat lung
  作者：Kazumi Shiosaki、Andrew S. Tasker、Gerard M. Sullivan、Bryan K. Sorensen、Thomas W. von Geldern、Jinshyun R. Wu-Wong、Carol A. Marselle、Terry J. Opgenorth

  DOI：10.1021/jm00056a007

  日期：1993.2

  Two structurally distinct series of potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme (ECE) activity identified in the rat lung have been developed. Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series. Alternatively, selected renin inhibitors containing the dihydroxyethylene moiety were shown to be inhibitors of rat lung activity. Subsequent modifications improved inhibition of the rat lung ECE while eliminating renin activity. Both series of ECE inhibitors demonstrated a range of selectivity over Cathepsin D. Water-solubilizing moieties were appended onto selected compounds to facilitate in vivo testing. Partial reduction of the pressor response to exogenously administered Big ET-1 was observed with selected rat lung ECE inhibitors.