ML188 | 1417699-67-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: ML188
• 英文别名: N-[2-(tert-butylamino)-2-oxo-1-pyridin-3-ylethyl]-N-(4-tert-butylphenyl)furan-2-carboxamide
• CAS: 1417699-67-2
• 化学式: C₂₆H₃₁N₃O₃
• 分子量: 433.55
• InChiKey: JXGIYKRRPGCLFV-UHFFFAOYSA-N

物化性质

• 沸点：
  630.7±55.0 °C(Predicted)
• 密度：
  1.142±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  75.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ML188 在 IA column 作用下， 以 甲醇 为溶剂， 生成 (R)-N-(4-(叔丁基)苯基)-N-(2-(叔丁基氨基)-2-氧代-1-(吡啶-3-基)乙基)呋喃-2-甲酰胺
  参考文献：
  名称：

  Discovery, Synthesis, And Structure-Based Optimization of a Series of N-(tert-Butyl)-2-(N-arylamido)-2-(pyridin-3-yl) Acetamides (ML188) as Potent Noncovalent Small Molecule Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease

  摘要：

  A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure-activity relationships within S-1, S-1, and S-2 enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.

  DOI：

  10.1021/jm301580n
• 作为产物：
  描述：

  3-吡啶甲醛 、 糠酸（呋喃甲酸） 、 异氰环已烷 、 4-叔丁基苯胺 以 甲醇 为溶剂， 反应 0.5h， 以84%的产率得到ML188
  参考文献：
  名称：

  新型 SARS-CoV-2 3CLpro 共价抑制剂的设计、合成和体外评价

  摘要：

  当前的 COVID-19 大流行以及之前的 SARS 和 MERS 爆发等严重疾病都是冠状病毒感染的结果，并表明迫切需要抗病毒药物来对抗这些致命病毒。由于其在病毒复制和功能中的重要作用，3CL pro （主要冠状病毒半胱氨酸蛋白酶）已被确定为开发抗病毒药物的有希望的靶标。之前报道的 SARS-CoV 3CL pro非共价抑制剂被用作开发 SARS-CoV-2 3CL pro共价抑制剂的起点。我们在此报告了当使用病毒蛋白酶的酶活性作为筛选平台时，我们在设计和合成亚微摩尔共价抑制剂方面所做的努力。

  DOI：

  10.1016/j.ejmech.2021.114046

文献信息

• Expedited Approach toward the Rational Design of Noncovalent SARS-CoV-2 Main Protease Inhibitors
  作者：Naoya Kitamura、Michael Dominic Sacco、Chunlong Ma、Yanmei Hu、Julia Alma Townsend、Xiangzhi Meng、Fushun Zhang、Xiujun Zhang、Mandy Ba、Tommy Szeto、Adis Kukuljac、Michael Thomas Marty、David Schultz、Sara Cherry、Yan Xiang、Yu Chen、Jun Wang

  DOI：10.1021/acs.jmedchem.1c00509

  日期：2022.2.24

  Mpro inhibitor GC376. Significantly, 23R is highly selective compared with covalent inhibitors such as GC376, especially toward host proteases. The cocrystal structure of SARS-CoV-2 Mpro with 23R revealed a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study discovered 23R, one of the most potent and selective noncovalent SARS-CoV-2 Mpro inhibitors reported

  SARS-CoV-2 的主要蛋白酶 (M pro ) 是经过验证的抗病毒药物靶点。据报道，几种 M pro抑制剂具有有效的酶抑制和细胞抗病毒活性，包括GC376 、 boceprevir 、钙蛋白酶抑制剂 II和XII ，每种抑制剂都含有共价修饰催化 Cys145 的反应弹头。将基于结构的药物设计与一锅 Ugi 四组分反应相结合，我们发现了最有效的非共价抑制剂之一23R ( Jun8-76-3A )，其结构与典型的 M pro抑制剂GC376不同。值得注意的是，与GC376等共价抑制剂相比， 23R具有高度选择性，尤其是针对宿主蛋白酶。 SARS-CoV-2 M pro与23R的共晶结构揭示了位于 S2 和 S4 口袋之间的先前未探索的结合位点。总体而言，这项研究发现了23R ，这是迄今为止报道的最有效和选择性最强的非共价 SARS-CoV-2 M pro抑制剂之一，以及 M pro中的一个新的结合口袋，可用于抑制剂设计。
• Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses
  作者：Andreas Luttens、Hjalmar Gullberg、Eldar Abdurakhmanov、Duy Duc Vo、Dario Akaberi、Vladimir O. Talibov、Natalia Nekhotiaeva、Laura Vangeel、Steven De Jonghe、Dirk Jochmans、Janina Krambrich、Ali Tas、Bo Lundgren、Ylva Gravenfors、Alexander J. Craig、Yoseph Atilaw、Anja Sandström、Lindon W. K. Moodie、Åke Lundkvist、Martijn J. van Hemert、Johan Neyts、Johan Lennerstrand、Jan Kihlberg、Kristian Sandberg、U. Helena Danielson、Jens Carlsson

  DOI：10.1021/jacs.1c08402

  日期：2022.2.23

  Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235

  在 COVID-19 大流行期间，针对 SARS-CoV-2 的药物可能挽救了数百万人的生命，现在开发冠状病毒复制抑制剂以应对未来的爆发至关重要。我们探索了两种虚拟筛选策略，以在超大型化学文库中寻找 SARS-CoV-2 主要蛋白酶的抑制剂。首先，基于结构的对接被用于筛选针对活性位点的 2.35 亿个虚拟化合物的多样化库。一百个排名靠前的化合物在结合和酶分析中进行了测试。其次，通过对数百万个精细分子的对接和93种化合物的实验测试，对晶体筛选发现的片段进行了优化。在第一个文库筛选中确定了三种抑制剂，其中五个选定的片段精化显示出抑制作用。
• NOVEL BIS-AMIDE DERIVATIVE AND USE THEREOF
  申请人：University-Industry Cooperation Group of Kyung Hee University

  公开号：EP3050871B1

  公开（公告）日：2018-11-07
• Discovery, Synthesis, And Structure-Based Optimization of a Series of <i>N</i>-(<i>tert</i>-Butyl)-2-(<i>N</i>-arylamido)-2-(pyridin-3-yl) Acetamides (ML188) as Potent Noncovalent Small Molecule Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease
  作者：Jon Jacobs、Valerie Grum-Tokars、Ya Zhou、Mark Turlington、S. Adrian Saldanha、Peter Chase、Aimee Eggler、Eric S. Dawson、Yahira M. Baez-Santos、Sakshi Tomar、Anna M. Mielech、Susan C. Baker、Craig W. Lindsley、Peter Hodder、Andrew Mesecar、Shaun R. Stauffer

  DOI：10.1021/jm301580n

  日期：2013.1.24

  A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure-activity relationships within S-1, S-1, and S-2 enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.
• Design, synthesis and in vitro evaluation of novel SARS-CoV-2 3CLpro covalent inhibitors
  作者：Julia K. Stille、Jevgenijs Tjutrins、Guanyu Wang、Felipe A. Venegas、Christopher Hennecker、Andrés M. Rueda、Itai Sharon、Nicole Blaine、Caitlin E. Miron、Sharon Pinus、Anne Labarre、Jessica Plescia、Mihai Burai Patrascu、Xiaocong Zhang、Alexander S. Wahba、Danielle Vlaho、Mitchell J. Huot、T. Martin Schmeing、Anthony K. Mittermaier、Nicolas Moitessier

  DOI：10.1016/j.ejmech.2021.114046

  日期：2022.2

  promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in the design and synthesis of submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

  当前的 COVID-19 大流行以及之前的 SARS 和 MERS 爆发等严重疾病都是冠状病毒感染的结果，并表明迫切需要抗病毒药物来对抗这些致命病毒。由于其在病毒复制和功能中的重要作用，3CL pro （主要冠状病毒半胱氨酸蛋白酶）已被确定为开发抗病毒药物的有希望的靶标。之前报道的 SARS-CoV 3CL pro非共价抑制剂被用作开发 SARS-CoV-2 3CL pro共价抑制剂的起点。我们在此报告了当使用病毒蛋白酶的酶活性作为筛选平台时，我们在设计和合成亚微摩尔共价抑制剂方面所做的努力。