(E)-4-(1-aminocyclobutyl)-N-[(2R)-1-[[(2R)-1-[4-(dimethylamino)piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]-methylamino]-3-naphthalen-2-yl-1-oxopropan-2-yl]-N-methylbut-2-enamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (E)-4-(1-aminocyclobutyl)-N-[(2R)-1-[[(2R)-1-[4-(dimethylamino)piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]-methylamino]-3-naphthalen-2-yl-1-oxopropan-2-yl]-N-methylbut-2-enamide
• 化学式: C₃₉H₅₁N₅O₃
• 分子量: 637.866
• InChiKey: VSPLCPUFQOSRFS-ATQVSBGGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  47
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  90.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  N-tert-butoxycarbonyl-N-methyl-D-phenylalanine 在 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 162.99h， 生成 (E)-4-(1-aminocyclobutyl)-N-[(2R)-1-[[(2R)-1-[4-(dimethylamino)piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]-methylamino]-3-naphthalen-2-yl-1-oxopropan-2-yl]-N-methylbut-2-enamide
  参考文献：
  名称：

  The influence of conformational restriction in the C-terminus of growth hormone secretagogues on their potency

  摘要：

  in order to obtain more potent growth hormone secretagogues, a comparison of ipamorelin and NN703 suggested the addition of a polar group at the C-terminus of NN703. A study was conducted using constrained amines for this purpose. Here, substituted 4-piperidinylamino- and 4-dimethylaminopiperidino-substitutents were found to give the most active compounds. A replacement of the 4-dimethylaminopiperidino-substituent with 4-hydroxypiperidino resulted in a series of compounds, which showed in vitro activity with EC50 values in the low nanomolar range, and favourable kinetic properties, such as 40% oral bioavailability. The most promising compound was also tested in a swine in vivo model, resulting in a growth hormone level with a C-max of over 40 ng mL(-1). (C) 2002 Editions scientifiques et medicales Elsevier SAS. All rights reserved..

  DOI：

  10.1016/s0223-5234(02)01370-3

文献信息

• [EN] COMPOUNDS WITH GROWTH HORMONE RELEASING PROPERTIES<br/>[FR] COMPOSES A PROPRIETES DE LIBERATION DE L'HORMONE DE CROISSANCE
  申请人：NOVO NORDISK AS

  公开号：WO2000001726A1

  公开（公告）日：2000-01-13

  The invention relates to novel compounds, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone.

  该发明涉及新型化合物、含有它们的组合物以及它们用于治疗由生长激素缺乏引起的医疗障碍的用途。
• Compounds with growth hormone releasing properties
  申请人：Peschke Bernd

  公开号：US20050233981A1

  公开（公告）日：2005-10-20

  Disclosed are compounds of formula I wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , G, J, L, M, a, b, c, d, e, and f are as defined in the specification, and compositions containing them. These compounds are useful for treating medical disorders resulting from a deficiency in growth hormone.

  本发明涉及一种公式I的化合物，其中R1、R2、R5、R6、R7、R8、G、J、L、M、a、b、c、d、e和f如规范中所定义，以及含有它们的组合物。这些化合物可用于治疗因生长激素缺乏引起的医学疾病。
• Use of inhibitors of glycogen synthase-3 to augment CD28 dependent -T-cell responses
  申请人：Rudd Christopher

  公开号：US20050075276A1

  公开（公告）日：2005-04-07

  The invention concerns the identification of a pathway where the co-receptor CD28 inactivates glycogen synthase 3 (GSK-3) and where a reagent that inhibits GSK-3 can enhance, or substitute for CD28-dependent T-cell mediated immune responses. Altered T-cell responses are applied to increased proliferation, cytokine production and in the generation of increased cytolytic T-cell responses (CTLs) in the context of infection by virus', bacterial, fungi or prions. For example, the use of GSK-3 inhibitor SB415286 preferentially cooperated with CD28 costimulation to increase interleukin 2 (IL-2) transcription, and to provide CD28-replacement signals leading to increased IL-2 transcription. Similarly, inhibitors SB415286 and lithium chloride increased the CD28-dependent generation of cytolytic T-cell responses (CTLs) against a virally or baterially infected cells. Overall, the invention relates to a CD28 induced signaling transduction pathway that inactivates glycogen synthase kinase (GSK) and the application of this finding to the modulation of T-cell activation, proliferation and the generation of cytolytic T-cells (CTLs).

  本发明涉及一种途径的鉴定，在该途径中，共受体 CD28 可使糖原合酶 3 (GSK-3) 失活，而抑制 GSK-3 的试剂可增强或替代 CD28 依赖性 T 细胞介导的免疫反应。在病毒、细菌、真菌或朊病毒感染的情况下，改变的 T 细胞反应可用于增加增殖、细胞因子的产生以及细胞溶解性 T 细胞反应（CTL）的产生。例如，使用 GSK-3 抑制剂 SB415286 可优先配合 CD28 成本刺激，增加白细胞介素 2（IL-2）转录，并提供 CD28 替代信号，导致 IL-2 转录增加。同样，抑制剂 SB415286 和氯化锂增加了 CD28 依赖性产生的针对病毒感染或双向感染细胞的细胞溶解性 T 细胞反应（CTL）。总之，本发明涉及一种 CD28 诱导的使糖原合酶激酶（GSK）失活的信号转导途径，以及将这一发现应用于调节 T 细胞的活化、增殖和细胞溶解性 T 细胞（CTL）的产生。
• COMPOUNDS WITH GROWTH HORMONE RELEASING PROPERTIES
  申请人：NOVO NORDISK A/S

  公开号：EP1100824A1

  公开（公告）日：2001-05-23
• Method of reducing C-reactive protein using growth hormone secretagogues
  申请人：Polvino J. William

  公开号：US20050261201A1

  公开（公告）日：2005-11-24

  The present invention relates to a method of reducing C-reactive protein in a subject in need of treatment thereof, wherein the subject is at risk of having or the subject has already had a vascular event or suffering from an inflammatory disease or disorder. In one embodiment, the vascular event is a cardiovascular event (e.g., myocardial infarction). In another embodiment, the vascular event is a cerebrovascular event (e.g., stroke (such as transient ischemic attacks (TIAs)). In yet another embodiment the vascular event is a peripheral vascular event (e.g., intermittent claudication). The method comprises administering a therapeutically effective amount of at least one growth hormone secretagogue compound or a pharmaceutically acceptable salt, hydrate or solvate thereof. The growth hormone secretagogue can be coadministered with a second growth hormone secretagogue, HMG CoA reductase inhibitor, an ACAT inhibitor, a CETP inhibitor, an anti-inflammatory agent, an ACE inhibitor, a Beta blocker, a cholesterol absorption inhibitor, a nicotonic acid, a fibric acid derivative, a bile acid sequestering agent or a combination thereof.