methyl (S)-3-cyclohexyl-2-isocyanatopropanoate | 40203-89-2

• 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: methyl (S)-3-cyclohexyl-2-isocyanatopropanoate
• 英文别名: methyl (2S)-3-cyclohexyl-2-isocyanatopropanoate
• CAS: 40203-89-2
• 化学式: C₁₁H₁₇NO₃
• 分子量: 211.261
• InChiKey: YFHJAPNUWGMZGH-JTQLQIEISA-N

物化性质

• 沸点：
  281.2±23.0 °C(Predicted)
• 密度：
  1.13±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  15
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  55.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl (S)-3-cyclohexyl-2-isocyanatopropanoate 在 三乙基硅烷 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 6.0h， 生成
  参考文献：
  名称：

  Synthesis and evaluation of potent, highly-selective, 3-aryl-piperazinone inhibitors of protein geranylgeranyltransferase-I

  摘要：

  基于PGGTase-I底物的羧端CAAL序列，设计并合成了一系列化合物。我们利用哌嗪-2-酮作为半刚性骨架，在明确有序的排列中引入了关键的药效团，以模拟CAAL序列。对于抑制PGGTase-I，如45和70结构所展现，其活性高且选择性极佳。这一系列GGTIs的活性依赖于具有自由羧端的L-亮氨酸残基以及3-芳基的S构型。通过咪唑环上的5-甲基取代和3-芳基上的氟取代，其选择性显著提升。发现对哌嗪酮骨架的6位进行修饰是不利的。化合物44和69，即45和70的相应甲酯，分别以0.4 µM和0.7 µM的IC50值选择性地阻断PGGTase-I对Rap1A的细胞内加工。

  DOI：

  10.1039/b517572k
• 作为产物：
  描述：

  L-环己基丙氨酸 在 氯化亚砜 、 三乙胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 3.0h， 生成 methyl (S)-3-cyclohexyl-2-isocyanatopropanoate
  参考文献：
  名称：

  Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure–Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies

  摘要：

  Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.

  DOI：

  10.1021/jm5019934

文献信息

• Design, Synthesis, and Evaluation of Novel Prodrugs of Transition State Inhibitors of Norovirus 3CL Protease
  作者：Anushka C. Galasiti Kankanamalage、Yunjeong Kim、Athri D. Rathnayake、Kevin R. Alliston、Michelle M. Butler、Steven C. Cardinale、Terry L. Bowlin、William C. Groutas、Kyeong-Ok Chang

  DOI：10.1021/acs.jmedchem.7b00497

  日期：2017.7.27

  Ester and carbamate prodrugs of aldehyde bisulfite adduct inhibitors were synthesized in order to improve their pharmacokinetic and pharmacodynamic properties. The inhibitory activity of the compounds against norovirus 3C-like protease in enzyme and cell-based assays was determined. The ester and carbamate prodrugs displayed equivalent potency to those of the precursor aldehyde bisulfite adducts and

  醛亚硫酸氢盐加合物抑制剂的酯和氨基甲酸酯前药被合成，以改善其药代动力学和药效学性质。在酶和基于细胞的测定中，确定了化合物对诺如病毒3C样蛋白酶的抑制活性。酯和氨基甲酸酯前药显示出与前体醛亚硫酸氢盐加合物和前体醛相同的效力。此外，发现酯的裂解速率取决于烷基链长。产生的前药显示出低细胞毒性和令人满意的肝微粒体稳定性和血浆蛋白结合。
• Design, synthesis, and evaluation of a novel series of macrocyclic inhibitors of norovirus 3CL protease
  作者：Vishnu C. Damalanka、Yunjeong Kim、Anushka C. Galasiti Kankanamalage、Gerald H. Lushington、Nurjahan Mehzabeen、Kevin P. Battaile、Scott Lovell、Kyeong-Ok Chang、William C. Groutas

  DOI：10.1016/j.ejmech.2016.12.033

  日期：2017.2

  novel class of macrocyclic inhibitors of norovirus 3C-like protease, a cysteine protease that is essential for virus replication. SAR, structural, and biochemical studies were carried out to ascertain the effect of structure on pharmacological activity and permeability. Insights gained from these studies have laid a solid foundation for capitalizing on the therapeutic potential of the series of inhibitors

  诺如病毒感染对全世界的公共卫生有重大影响，但目前尚缺乏诺如病毒特有的疗法和预防措施。这份报告描述了新型的诺如病毒3C样蛋白酶的大环抑制剂的发现，这是一种对病毒复制至关重要的半胱氨酸蛋白酶。进行了SAR，结构和生化研究，以确定结构对药理活性和通透性的影响。从这些研究中获得的见解为利用本文所述的一系列抑制剂的治疗潜力奠定了坚实的基础。
• Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin
  作者：Vishnu C. Damalanka、Scott A. Wildman、James W. Janetka

  DOI：10.1039/c9md00234k

  日期：——

  Matriptase and hepsin are type II transmembrane serine proteases (TTSPs). Along with related S1 trypsin like serine protease HGFA (hepatocyte growth factor activator), their unregulated proteolytic activity has been associated with cancer including tumor progression and metastasis. These three proteases have two substrates in common, hepatocyte growth factor (HGF) and macrophage stimulating protein

  Matriptase和hepsin是II型跨膜丝氨酸蛋白酶（TTSPs）。连同相关的S1胰蛋白酶，如丝氨酸蛋白酶HGFA（肝细胞生长因子激活剂）一样，它们不受调节的蛋白水解活性也与癌症有关，包括肿瘤进展和转移。这三种蛋白酶具有两个共同的底物，即肝细胞生长因子（HGF）和巨噬细胞刺激蛋白（MSP），MET的配体和南tai受体（RON）受体酪氨酸激酶。这些蛋白酶的基于机理的四肽和苯甲idine抑制剂已被证明可阻断HGF / MET和MSP / RON癌细胞的信号传导。在这里，我们合理地设计了一种新型的拟肽杂合小分子氨基甲酸哌啶氨基甲酸酯二肽抑制剂，其功效可与更大的四肽媲美。
• 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。
• Inhibition of norovirus 3CL protease by bisulfite adducts of transition state inhibitors
  作者：Sivakoteswara Rao Mandadapu、Mallikarjuna Reddy Gunnam、Kok-Chuan Tiew、Roxanne Adeline Z. Uy、Allan M. Prior、Kevin R. Alliston、Duy H. Hua、Yunjeong Kim、Kyeong-Ok Chang、William C. Groutas

  DOI：10.1016/j.bmcl.2012.11.026

  日期：2013.1

  Noroviruses are the most common cause of acute viral gastroenteritis, accounting for >21 million cases annually in the US alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this study, a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and alpha-ketoamides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED50 of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition state inhibitors in the inhibition of norovirus 3C-like protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as alpha-ketoheterocycles and alpha-ketoesters. (C) 2012 Elsevier Ltd. All rights reserved.