(-)N-[1-{N’-cyano-N-[3-(difluoromethoxy)phenyl]carbamimidoyl}-3-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-4-yl]-N-ethyl-2-hydroxyacetamide

• 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: (-)N-[1-{N’-cyano-N-[3-(difluoromethoxy)phenyl]carbamimidoyl}-3-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-4-yl]-N-ethyl-2-hydroxyacetamide
• 英文别名: BAY-598 R-isomer；N-[(4R)-2-[N-cyano-N'-[3-(difluoromethoxy)phenyl]carbamimidoyl]-5-(3,4-dichlorophenyl)-3,4-dihydropyrazol-4-yl]-N-ethyl-2-hydroxyacetamide
• 化学式: C₂₂H₂₀Cl₂F₂N₆O₃
• 分子量: 525.342
• InChiKey: OTTJIRVZJJGFTK-GOSISDBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  35
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2-(3,4-二氯苯基)-2-氧代乙胺盐酸盐 在 sodium tetrahydroborate 、 四(三苯基膦)钯 、 正丁基锂 、 1,3-二甲基巴比妥酸 、 碳酸氢钠 、 potassium carbonate 、 一水合肼 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 正己烷 、 二氯甲烷 、 水 、 异丙醇 为溶剂， 反应 8.08h， 生成 BAY-598 、 (-)N-[1-{N’-cyano-N-[3-(difluoromethoxy)phenyl]carbamimidoyl}-3-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-4-yl]-N-ethyl-2-hydroxyacetamide
  参考文献：
  名称：

  Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2

  摘要：

  Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood. Utilisation of highly potent and selective chemical probes for target validation has emerged as a concept which circumvents possible limitations of knockdown experiments and, in particular, could result in an improved exploration of drug targets with a complex underlying biology. Here, we report the development of a potent, selective, and cell-active, substrate-competitive inhibitor of SMYD2, which is the first reported inhibitor suitable for in vivo target validation studies in rodents.

  DOI：

  10.1021/acs.jmedchem.5b01890

文献信息

• [EN] NOVEL ARYL-CYANOGUANIDINE COMPOUNDS<br/>[FR] NOUVEAUX COMPOSÉS D'ARYL-CYANOGUANIDINE
  申请人：BAYER PHARMA AG

  公开号：WO2016091845A1

  公开（公告）日：2016-06-16

  The present invention relates to protein-lysine N-methyltransferase SMYD2 (SET and MYND domain-containing protein 2) inhibitors, in particular SMYD2-inhibitory substituted cyanoguanidine-pyrazolines of general formula (I) wherein R1, R2, R3, R4, R5, X and r have the meaning as described and defined herein, as well as to pharmaceutical compositions comprising compounds according to the invention and to their prophylactic and therapeutic use for hyperproliferative disorders, in particular for cancer, respectively tumour disorders. The present invention furthermore relates to the use of SMYD2 inhibitors for benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, neurodegenerative disorders, inflammatory disorders, atherosclerotic disorders and the control of male fertility.

  本发明涉及蛋白赖氨酸N-甲基转移酶SMYD2（SET和MYND结构域含蛋白2）抑制剂，特别是通式（I）所示的SMYD2抑制剂取代的氰胍基吡唑啉化合物，其中R1、R2、R3、R4、R5、X和r具有如下所述和定义的含义，以及包含根据本发明的化合物的药物组合物，以及它们在高增殖性疾病，特别是癌症，以及肿瘤疾病的预防和治疗中的应用。本发明还涉及将SMYD2抑制剂用于良性增生、动脉粥样硬化疾病、败血症、自身免疫性疾病、血管疾病、病毒感染、神经退行性疾病、炎症性疾病、动脉粥样硬化疾病和男性生育能力的控制。
• Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2
  作者：Erik Eggert、Roman C. Hillig、Silke Koehr、Detlef Stöckigt、Jörg Weiske、Naomi Barak、Jeffrey Mowat、Thomas Brumby、Clara D. Christ、Antonius ter Laak、Tina Lang、Amaury E. Fernandez-Montalvan、Volker Badock、Hilmar Weinmann、Ingo V. Hartung、Dalia Barsyte-Lovejoy、Magdalena Szewczyk、Steven Kennedy、Fengling Li、Masoud Vedadi、Peter J. Brown、Vijayaratnam Santhakumar、Cheryl H. Arrowsmith、Timo Stellfeld、Carlo Stresemann

  DOI：10.1021/acs.jmedchem.5b01890

  日期：2016.5.26

  Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood. Utilisation of highly potent and selective chemical probes for target validation has emerged as a concept which circumvents possible limitations of knockdown experiments and, in particular, could result in an improved exploration of drug targets with a complex underlying biology. Here, we report the development of a potent, selective, and cell-active, substrate-competitive inhibitor of SMYD2, which is the first reported inhibitor suitable for in vivo target validation studies in rodents.