CAY 10398 | 193551-00-7

• 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: CAY 10398
• 英文别名: (4-(dimethylamino)-N-(6-hydroxyamino)-6-oxohexyl)benzamide；4-(Dimethylamino)-N-[6-(hydroxyamino)-6-oxohexyl]-benzamide；4-(dimethylamino)-N-[6-(hydroxyamino)-6-oxohexyl]benzamide
• CAS: 193551-00-7
• 化学式: C₁₅H₂₃N₃O₃
• 分子量: 293.366
• InChiKey: RGWSSTALGUXZMU-UHFFFAOYSA-N

物化性质

• 溶解度：
  DMF：20mg/mL； DMF:PBS (pH 7.2) (1:5)：300 μg/ml； DMSO：14mg/mL；乙醇：1mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  21
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  81.7
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  叔丁氧羰酰基6-氨基己酸 在 10percent Pd/C N-甲基吗啉 、 三乙基硅烷 、 三氟乙酸 、 4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 环己烷 为溶剂， 反应 27.5h， 生成 CAY 10398
  参考文献：
  名称：

  An Easy and Convenient Synthesis of Weinreb Amides and Hydroxamates

  摘要：

  DOI：

  10.1021/jo015524b

文献信息

• Carbamic acid compounds comprising an amide linkage as hdac inhibitors
  申请人：——

  公开号：US20040092598A1

  公开（公告）日：2004-05-13

  This invention pertains to certain active carbamic acid compounds which inhibit HDAC activity and which have the formula (1) wherein: A is an aryl group; Q1 is an aryl leader group having a backbone of at least 2 carbon atoms; J is an amide linkage selected from: —NR1C(═O)—and —C(═O)NR1—; R1 is an amido substituent; and, Q2 is an acid leader group; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC, and, e.g., to inhibit proliferative conditions, such as cancer and psoriasis.

  这项发明涉及抑制HDAC活性的某些活性碳酸酰胺化合物，其化学式为（1），其中：A是芳基；Q1是至少有2个碳原子骨架的芳基前导基团；J是选择自以下的酰胺键：—NR1C(═O)—和—C(═O)NR1—；R1是酰胺取代基；Q2是酸前导基团；以及其药学上可接受的盐、溶剂化合物、酰胺、酯、醚、化学保护形式和前药。本发明还涉及包含这种化合物的药物组合物，以及在体外和体内使用这种化合物和组合物来抑制HDAC，例如，抑制增殖性疾病，如癌症和牛皮癣。
• A Metabolic Screening Study of Trichostatin A (TSA) and TSA-Like Histone Deacetylase Inhibitors in Rat and Human Primary Hepatocyte Cultures
  作者：G. Elaut、G. Laus、E. Alexandre、L. Richert、P. Bachellier、D. Tourwé、V. Rogiers、T. Vanhaecke

  DOI：10.1124/jpet.106.116202

  日期：2007.4

  Hydroxamic acid (HA)-based histone deacetylase (HDAC) inhibitors, with trichostatin A (TSA) as the reference compound, are potential antitumoral drugs and show promise in the creation of long-term primary cell cultures. However, their metabolic properties have barely been investigated. TSA is rapidly inactivated in rodents both in vitro and in vivo. We previously found that 5-(4-dimethylaminobenzoyl)aminovaleric acid hydroxyamide or 4-Me2 N -BAVAH (compound 1 ) is metabolically more stable upon incubation with rat hepatocyte suspensions. In this study, we show that human hepatocytes also metabolize TSA more rapidly than compound 1 and that similar pathways are involved. Furthermore, structural analogs of compound 1 (compounds 2 - 9 ) are reported to have the same favorable metabolic properties. Removal of the dimethylamino substituent of compound 1 creates a very stable but 50% less potent inhibitor. Chain lengthening (4 to 5 carbon spacer) slightly improves both potency and metabolic stability, favoring HA reduction to hydrolysis. On the other hand, Cα-unsaturation and spacer methylation not only reduce HDAC inhibition but also increase the rate of metabolic inactivation approximately 2-fold, mainly through HA reduction. However, in rat hepatocyte monolayer cultures, compound 1 is shown to be extensively metabolized by phase II conjugation. In conclusion, this study suggests that simple structural modifications of amide-linked TSA analogs can improve their phase I metabolic stability in both rat and human hepatocyte suspensions. Phase II glucuronidation, however, can compensate for their lower phase I metabolism in rat hepatocyte monolayers and could play a yet unidentified role in the determination of their in vivo clearance.

  基于羟肟酸（HA）的组蛋白去乙酰化酶（HDAC）抑制剂，以三氢司他丁 A（TSA）为参照化合物，是一种潜在的抗肿瘤药物，在建立长期原代细胞培养物方面显示出前景。然而，对它们的代谢特性几乎没有进行过研究。TSA 在啮齿动物体内外都会迅速失活。我们之前发现，5-（4-二甲氨基苯甲酰基）氨基戊酸羟酰胺或 4-Me2 N -BAVAH（化合物 1）与大鼠肝细胞悬浮液培养后的代谢更稳定。在本研究中，我们发现人类肝细胞代谢 TSA 的速度也比化合物 1 快，而且涉及类似的途径。此外，据报道化合物 1 的结构类似物（化合物 2 - 9）也具有相同的良好代谢特性。去掉化合物 1 的二甲基氨基取代基后，会产生一种非常稳定的抑制剂，但药效会降低 50%。延长链（4 到 5 个碳间隔）可略微提高药效和代谢稳定性，使 HA 减少水解。另一方面，Cα-不饱和和间隔甲基化不仅会降低 HDAC 抑制作用，还会使代谢失活率提高约 2 倍，主要是通过 HA 还原。不过，在大鼠肝细胞单层培养物中，化合物 1 通过 II 期共轭作用被广泛代谢。总之，这项研究表明，对酰胺连接的 TSA 类似物进行简单的结构修饰就能提高它们在大鼠和人类肝细胞悬浮液中的 I 期代谢稳定性。然而，II 期葡糖醛酸化作用可弥补其在大鼠肝细胞单层中较低的 I 期代谢，并可在确定其体内清除率方面发挥尚未确定的作用。
• CARBAMIC ACID COMPOUNDS COMPRISING AN AMIDE LINKAGE AS HDAC INHIBITORS
  申请人：Watkins Clare J.

  公开号：US20110105572A1

  公开（公告）日：2011-05-05

  This invention pertains to certain active carbamic acid compounds which inhibit HDAC activity and which have the following formula: wherein: A is a C 5-20 heteroaryl or C 5-20 carboaryl group and is optionally substituted; Q 1 is a C 2-7 alkylene group having a backbone of at least 2 carbon atoms, and is optionally substituted; J is —N(R 1 )C(═O)— or —C(═O)N(R 1 )—; R 1 is hydrogen, C 1-7 alkyl, C 3-20 heterocyclyl, or C 5-20 aryl; and, Q 2 is C 1-7 alkylene, C 5-20 arylene, C 5-20 arylene-C 1-7 alkylene, or C 1-7 alkylene-C 5-20 arylene having a backbone of at least 3 carbon atoms, and is optionally substituted; and pharmaceutically acceptable salts thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC, and, e.g., to treat proliferative conditions, such as cancer and psoriasis.

  本发明涉及某些活性碳酰胺酸化合物，其抑制HDAC活性，并具有以下公式：其中：A是C5-20杂环芳基或C5-20羰基芳基基团，并可选择性地取代；Q1是具有至少2个碳原子的C2-7烷基链，可选择性地取代；J是-N（R1）C（═O）-或-C（═O）N（R1）-；R1是氢，C1-7烷基，C3-20杂环芳基或C5-20芳基；Q2是具有至少3个碳原子的C1-7烷基链，C5-20芳基链，C5-20芳基链-C1-7烷基链，或C1-7烷基链-C5-20芳基链，并可选择性地取代；以及其药学上可接受的盐。本发明还涉及包含这种化合物的制药组合物，以及使用这种化合物和组合物在体内外抑制HDAC，例如治疗增殖性疾病，如癌症和牛皮癣。
• INHIBITORS OF HISTONE DEACETYLASE
  申请人：DANA-FARBER CANCER INSTITUTE, INC.

  公开号：US20160272579A1

  公开（公告）日：2016-09-22

  The present invention relates to compounds which inhibit histone deacetylase activity and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing these compounds. The present invention also relates to methods of treating and preventing hematological cell proliferative disorders, such as multiple myeloma, by administering these compounds and pharmaceutical compositions to subjects in need thereof.

  本发明涉及抑制组蛋白去乙酰化酶活性的化合物及其合成方法。本发明还涉及含有这些化合物的制药组合物。本发明还涉及通过向需要治疗和预防血液细胞增殖性疾病（如多发性骨髓瘤）的受试者给予这些化合物和制药组合物的方法。
• Carbamic acid compounds comprising an amide linkage as HDAC inhibitors
  申请人：TopoTarget UK Limited

  公开号：EP1598067A1

  公开（公告）日：2005-11-23

  This invention pertains to certain active carbamic acid compounds which inhibit HDAC activity and which have the following formula: wherein: A is an aryl group; Q1 is an aryl leader group having a backbone of at least 2 carbon atoms; J is an amide linkage selected from: -NR1C(=O)- and -C(=O)NR1-; R1 is an amido substituent; and, Q2 is an acid leader group; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof, for use in the treatment of parasitic infections, such as malaria.

  本发明涉及某些抑制 HDAC 活性的活性氨基甲酸化合物，它们具有下式： 其中A是芳基；Q1是具有至少2个碳原子骨架的芳基领导基团；J是选自-NR1C(＝O)-和-C(＝O)NR1-的酰胺连接；R1是氨基取代基；Q2是酸领导基团；及其药学上可接受的盐、溶液剂、酰胺、酯、醚、化学保护形式和原药，用于治疗寄生虫感染，如疟疾。