(4-[1,1-联苯]-4-基-1H-1,2,3-噻唑-1-基)[2-(苯基甲基)-1-哌啶基]-甲酮 | 1402612-55-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: (4-[1,1-联苯]-4-基-1H-1,2,3-噻唑-1-基)[2-(苯基甲基)-1-哌啶基]-甲酮
• 英文名称: KT109
• 英文别名: (4-([1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)(2-benzylpiperidin-1-yl)methanone；(4-([1,1′-biphenyl]4-yl)-1H-1,2,3-triazol-1-yl)(2-benzylpiperidin-1-yl)methanone；Methanone, (4-[1,1'-biphenyl]-4-yl-1H-1,2,3-triazol-1-yl)[2-(phenylMethyl)-1-piperidinyl]-；(2-benzylpiperidin-1-yl)-[4-(4-phenylphenyl)triazol-1-yl]methanone
• CAS: 1402612-55-8
• 化学式: C₂₇H₂₆N₄O
• 分子量: 422.53
• InChiKey: JKJMWHULJIOKPJ-UHFFFAOYSA-N

物化性质

• 沸点：
  637.3±53.0 °C(Predicted)
• 密度：
  1.19±0.1 g/cm3(Predicted)
• 溶解度：
  DMF:10.0(最大浓度 mg/mL);23.67(最大浓度 mM)DMSO:10.0(最大浓度 mg/mL);23.67(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  51
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  2-苄基哌啶 在 4-二甲氨基吡啶 、 sodium carbonate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 (4-[1,1-联苯]-4-基-1H-1,2,3-噻唑-1-基)[2-(苯基甲基)-1-哌啶基]-甲酮
  参考文献：
  名称：

  结构动力学关系和分子动力学显示不可逆的二酰基甘油脂肪酶抑制剂中杂环离去基团的关键作用。

  摘要：

  共价不可逆的，基于机理的酶抑制剂的药物发现计划通常着重于通过生化测定中IC50值确定的效价优化。这些测定不允许将结合活性（Ki）和反应性（运动）表征为共价抑制剂的各个动力学参数。在这里，我们报告动力学底物测定法的发展，以研究三唑脲衍生物作为二酰基甘油脂肪酶（DAGL）-α抑制剂的杂环离去基团的酸度（pKa）的影响。令人惊讶地，我们发现抑制剂的反应性与离去基团的pKa不相关，而杂环核中氮原子的位置在很大程度上决定了抑制剂的结合活性。通过共价键合的Michaelis-Menten配合物的分子动力学模拟证实并澄清了这一发现。希望对共价丝氨酸水解酶抑制剂的结合特性有更深入的了解，有助于发现和开发更具选择性的共价抑制剂。

  DOI：

  10.1021/acs.jmedchem.9b00686

文献信息

• [FR] INHIBITEURS DES SÉRINE HYDROLASES DE TYPE N1- ET N2-CARBAMOYL-1,2,3-TRIAZOLE ET MÉTHODES ASSOCIÉES
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2012138877A1

  公开（公告）日：2012-10-11

  The present invention provides inhibitors of a wide variety of serine hydrolase enzymes. The inhibitors of the present invention are N1- and N2-carbamoyl-1,2,3-triazole compounds such as those of Formula (I): (Formula (I)) in which N1, N2 and N3 are the nitrogen atoms at positions 1, 2, and 3, respectively, of the triazole ring, and R4, R5, R6, and R7 in Formula (I) are as described herein. Methods of inhibiting serine hydrolase enzymes and methods of preparing carbamoyl-1,2,3-triazole compounds also are described.

  本发明提供了多种丝氨酸水解酶的抑制剂。本发明的抑制剂是N1-和N2-羰胺基-1,2,3-三唑化合物，如式（I）所示：（式（I）），其中N1、N2和N3分别为三唑环的1、2和3位置的氮原子，式（I）中的R4、R5、R6和R7如本文所述。还描述了抑制丝氨酸水解酶酶和制备羰胺基-1,2,3-三唑化合物的方法。
• N1- and N2-CARBAMOYL-1,2,3-TRIAZOLE SERINE HYDROLASE INHIBITORS AND METHODS
  申请人：Cravatt Benjamin

  公开号：US20140018318A1

  公开（公告）日：2014-01-16

  The present invention provides inhibitors of a wide variety of serine hydrolase enzymes. The inhibitors of the present invention are N1- and N2-carbamoyl-1,2,3-triazole compounds such as those of Formula (I): in which N1, N2, and N3 are the nitrogen atoms at positions 1, 2, and 3, respectively, of the triazole ring, and R 4 , R 5 , R 6 and R 7 in Formula (I) are as described herein. Methods of inhibiting serine hydrolase enzymes and methods of preparing carbamoyl-1,2,3-triazole compounds also are described.

  本发明提供了一种广泛的丝氨酸水解酶酶抑制剂。本发明的抑制剂是N1-和N2-氨基甲酰基-1,2,3-三唑化合物，例如公式（I）中的化合物：其中N1、N2和N3是三唑环的1、2和3位置的氮原子，公式（I）中的R4、R5、R6和R7如本文所述。还描述了抑制丝氨酸水解酶的方法和制备氨基甲酰基-1,2,3-三唑化合物的方法。
• Development and Optimization of Piperidyl-1,2,3-Triazole Ureas as Selective Chemical Probes of Endocannabinoid Biosynthesis
  作者：Ku-Lung Hsu、Katsunori Tsuboi、Landon R. Whitby、Anna E. Speers、Holly Pugh、Jordon Inloes、Benjamin F. Cravatt

  DOI：10.1021/jm400898x

  日期：2013.11.14

  We have previously shown that 1,2,3-triazole ureas (1,2,3-TUs) act as versatile class of irreversible serine hydrolase inhibitors that can be tuned to create selective probes for diverse members of this large enzyme class, including diacylglycerol lipase-beta (DAGL beta), a principal biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). Here, we provide a detailed account of the discovery, synthesis, and structure-activity relationship (SAR) of (2-substituted)-piperidyl-1,2,3-TUs that selectively inactivate DAGL beta in living systems. Key to success was the use of activity-based protein profiling (ABPP) with broad-spectrum and tailored activity-based probes to guide our medicinal chemistry efforts. We also describe an expanded repertoire of DAGL-tailored activity-based probes that includes biotinylated and alkyne agents for enzyme enrichment coupled with mass spectrometry-based proteomics and assessment of proteome-wide selectivity. Our findings highlight the broad utility of 1,2,3-TUs for serine hydrolase inhibitor development and their application to create selective probes of endocannabinoid biosynthetic pathways.
• US9108930B2
  申请人：——

  公开号：US9108930B2

  公开（公告）日：2015-08-18
• Structure Kinetics Relationships and Molecular Dynamics Show Crucial Role for Heterocycle Leaving Group in Irreversible Diacylglycerol Lipase Inhibitors
  作者：Antonius P.A. Janssen、Jacob M.A. van Hengst、Olivier J.M. Béquignon、Hui Deng、Gerard J.P. van Westen、Mario van der Stelt

  DOI：10.1021/acs.jmedchem.9b00686

  日期：2019.9.12

  heterocyclic leaving group of triazole urea derivatives as diacylglycerol lipase (DAGL)-α inhibitors. Surprisingly, we found that the reactivity of the inhibitors did not correlate with the pKa of the leaving group, whereas the position of the nitrogen atoms in the heterocyclic core determined to a large extent the binding activity of the inhibitor. This finding was confirmed and clarified by molecular dynamics

  共价不可逆的，基于机理的酶抑制剂的药物发现计划通常着重于通过生化测定中IC50值确定的效价优化。这些测定不允许将结合活性（Ki）和反应性（运动）表征为共价抑制剂的各个动力学参数。在这里，我们报告动力学底物测定法的发展，以研究三唑脲衍生物作为二酰基甘油脂肪酶（DAGL）-α抑制剂的杂环离去基团的酸度（pKa）的影响。令人惊讶地，我们发现抑制剂的反应性与离去基团的pKa不相关，而杂环核中氮原子的位置在很大程度上决定了抑制剂的结合活性。通过共价键合的Michaelis-Menten配合物的分子动力学模拟证实并澄清了这一发现。希望对共价丝氨酸水解酶抑制剂的结合特性有更深入的了解，有助于发现和开发更具选择性的共价抑制剂。