N-(4,6-dimethylpyridin-2-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)-piperazine-1-carbothioamide trifluoroacetate | 1542213-65-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N-(4,6-dimethylpyridin-2-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)-piperazine-1-carbothioamide trifluoroacetate
• 英文别名: N-(4,6-dimethylpyridin-2-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbothioamide trifluoroacetate salt；NCT-502；N-(4,6-dimethylpyridin-2-yl)-4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-1-carbothioamide;2,2,2-trifluoroacetic acid
• CAS: 1542213-65-9
• 化学式: C₂HF₃O₂*C₁₈H₂₀F₃N₅S
• 分子量: 509.475
• InChiKey: DQKHMDFKAGKAJB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.26
• 重原子数：
  34
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  2-氨基-4,6-二甲基吡啶 以 四氢呋喃 为溶剂， 反应 1.58h， 生成 N-(4,6-dimethylpyridin-2-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)-piperazine-1-carbothioamide trifluoroacetate
  参考文献：
  名称：

  Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors

  摘要：

  Proliferating cells, including cancer cells, obtain serine both exogenously and via the metabolism of glucose. By catalyzing the first, rate-limiting step in the synthesis of serine from glucose, phosphoglycerate dehydrogenase (PHGDH) controls flux through the biosynthetic pathway for this important amino acid and represents a putative target in oncology. To discover inhibitors of PHGDH, a coupled biochemical assay was developed and optimized to enable high-throughput screening for inhibitors of human PHGDH. Feedback inhibition was minimized by coupling PHGDH activity to two downstream enzymes (PSAT1 and PSPH), providing a marked improvement in enzymatic turnover. Further coupling of NADH to a diaphorase/resazurin system enabled a red-shifted detection readout, minimizing interference due to compound autofluorescence. With this protocol, over 400,000 small molecules were screened for PHGDH inhibition, and following hit validation and triage work, a piperazine-1-thiourea was identified. Following rounds of medicinal chemistry and SAR exploration, two probes (NCT-502 and NCT-503) were identified. These molecules demonstrated improved target activity and encouraging ADME properties, enabling in vitro assessment of the biological importance of PHGDH, and its role in the fate of serine in PHGDH-dependent cancer cells. This manuscript reports the assay development and medicinal chemistry leading to the development of NCT-502 and -503 reported in Pacold et al. (2016). (C) 2018 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2018.02.016

文献信息

• Inhibitors of phosphoglycerate dehydrogenase (PHGDH) and uses thereof
  申请人：Whitehead Institute for Biomedical Research

  公开号：US11225469B2

  公开（公告）日：2022-01-18

  The present invention provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, pro-drugs, and compositions thereof. Also provided are methods and kits involving the compounds of Formula (I), (II) or (III) for treating diseases associated with the over-expression of phosphoglycerate dehydrogenase (PHGDH) in a subject, such as proliferative diseases (e.g., cancers (e.g., breast cancer, ER negative breast cancer, melanoma, cervical cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases). Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the activity of PHGDH or inhibit the serine biosynthetic pathway, or both.

  本发明提供了式(II)化合物及其药学上可接受的盐、溶液剂、水合物、多晶型、共晶体、同分异构体、立体异构体、同位素标记的衍生物、原药及其组合物。还提供了涉及式(I)、(II)或(III)化合物的方法和试剂盒，用于治疗与受试者体内磷酸甘油脱氢酶（PHGDH）过度表达有关的疾病，如增殖性疾病（如癌症（如乳腺癌、ER阴性乳腺癌、黑色素瘤、宫颈癌）、良性肿瘤、与血管生成有关的疾病、炎症性疾病、自身炎症性疾病和自身免疫性疾病）。使用本发明的化合物或组合物治疗增殖性疾病患者，可抑制 PHGDH 的活性或抑制丝氨酸生物合成途径，或两者兼而有之。
• 4-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-<i>N</i>-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide (ML267), a Potent Inhibitor of Bacterial Phosphopantetheinyl Transferase That Attenuates Secondary Metabolism and Thwarts Bacterial Growth
  作者：Timothy L. Foley、Ganesha Rai、Adam Yasgar、Thomas Daniel、Heather L. Baker、Matias Attene-Ramos、Nicolas M. Kosa、William Leister、Michael D. Burkart、Ajit Jadhav、Anton Simeonov、David J. Maloney

  DOI：10.1021/jm401752p

  日期：2014.2.13

  4'-Phosphopantetheinyl transferases (PPTases) catalyze a post-translational modification essential to bacterial cell viability and virulence. We present the discovery and medicinal chemistry optimization of 2-pyridinyl-N-(4-aryl)-piperazine-1-carbothioamides, which exhibit submicromolar inhibition of bacterial Sfp-PPTase with no activity toward the human orthologue. Moreover, compounds within this class possess antibacterial activity in the absence of a rapid cytotoxic response in human cells. An advanced analogue of this series, ML267 (55), was found to attenuate production of an Sfp-PPTase-dependent metabolite when applied to Bacillus subtilis at sublethal doses. Additional testing revealed antibacterial activity against methicillin-resistant Staphylococcus aureus, and chemical genetic studies implicated efflux as a mechanism for resistance in Escherichia coli. Additionally, we highlight the in vitro absorption, distribution, metabolism; and excretion and in vivo pharmacokinetic profiles of compound 55 to further demonstrate the potential utility of this small-molecule inhibitor.
• INHIBITORS OF PHOSPHOGLYCERATE DEHYDROGENASE (PHGDH) AND USES THEREOF
  申请人：Whitehead Institute for Biomedical Research

  公开号：US20180105508A1

  公开（公告）日：2018-04-19

  The present invention provides compounds pounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, pro-drugs, and compositions thereof. Also provided are methods and kits involving the compounds of Formula (I), (II) or (III) for treating diseases associated with the over-expression of phosphoglycerate dehydrogenase (PHGDH) in a subject, such as proliferative diseases (e.g., cancers (e.g., breast cancer, ER negative breast cancer, melanoma, cervical cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases). Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the activity of PHGDH or inhibit the serine biosynthetic pathway, or both.
• [EN] INHIBITORS OF PHOSPHOGLYCERATE DEHYDROGENASE (PHGDH) AND USES THEREOF<br/>[FR] INHIBITEURS DE PHOSPHOGLYCÉRATE DÉSHYDROGÉNASE (PHGDH) ET UTILISATIONS ASSOCIÉES
  申请人：WHITEHEAD BIOMEDICAL INST

  公开号：WO2016115463A1

  公开（公告）日：2016-07-21

  The present invention provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, pro-drugs, and compositions thereof. Also provided are methods and kits involving the compounds of Formula (I), (II) or (III) for treating diseases associated with the over-expression of phosphoglycerate dehydrogenase (PHGDH) in a subject, such as proliferative diseases (e.g., cancers (e.g., breast cancer, ER negative breast cancer, melanoma, cervical cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases). Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the activity of PHGDH or inhibit the serine biosynthetic pathway, or both.