8-[4-(1-氨基环丁基)苯基]-9-苯基-1,2,4-噻唑并[3,4-f][1,6]萘啶-3(2H)-酮双盐酸盐 | 1032350-13-2

• 物质功能分类: 生物化工 - 抑制剂 - PI3K/Akt/mTOR抑制剂(PI3K/Akt/mTOR)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 8-[4-(1-氨基环丁基)苯基]-9-苯基-1,2,4-噻唑并[3,4-f][1,6]萘啶-3(2H)-酮双盐酸盐
• 中文别名: 8-[4-(1-氨基环丁基)苯基]-9-苯基-1,2,4-三唑并[3,4-f][1,6]萘啶-3(2H)-酮二盐酸盐
• 英文名称: MK-2206 dihydrochloride
• 英文别名: 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one;dihydrochloride
• CAS: 1032350-13-2
• 化学式: C25H23Cl2N5O
• 分子量: 480.4
• InChiKey: HWUHTJIKQZZBRA-UHFFFAOYSA-N

物化性质

• 熔点：
  >255°C (dec.)
• 溶解度：
  可溶于 DMSO（升温时高达 10 mg/ml）

计算性质

• 辛醇/水分配系数(LogP)：
  5.09
• 重原子数：
  33
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  83.6
• 氢给体数：
  4
• 氢受体数：
  4

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

药理作用

MK-2206 2HCl是由美国默克公司研究发现的第一个进入临床阶段的Akt小分子变构抑制剂。最初的研究人员筛选发现，除了具有一定的Akt抑制活性外，它还对不同亚型的Akt有选择性。在未激活前，Akt主要以“PH-in”的构象存在，其磷酸激酶催化区与结构域处于折叠状态，并通过短肽Link上的变构位点产生特殊交互。而MK-2206 2HCl能与此变构位点结合，锁定Akt的“PH-in”状态，限制其构象改变，从而抑制Akt激活，阻止Akt调节的下游信号分子（如结节性硬化症2蛋白、PRAS40及核糖体S6蛋白）磷酸化。

生物活性

MK-2206 2HCl是一种高度选择性的Akt1/2/3抑制剂，在无细胞试验中IC50分别为8 nM/12 nM/65 nM；对其他250种蛋白激酶没有抑制作用。它在第二期临床试验（Phase 2）中有良好的表现，能够诱导肿瘤细胞自噬和凋亡。

特征

MK-2206是第一个进入临床阶段的Akt小分子变构抑制剂。

生物活性

MK-2206 2HCl是一种高度选择性的Akt1/2/3抑制剂，在无细胞试验中IC50分别为8 nM/12 nM/65 nM；对其他250种蛋白激酶没有抑制作用。它不仅能够诱导肿瘤细胞自噬和凋亡，还在第二期临床试验（Phase 2）中有显著效果。

靶点

Target	Value
Akt1 (Cell-free assay)	8 nM
Akt2 (Cell-free assay)	12 nM
Akt3 (Cell-free assay)	65 nM

体外研究

MK-2206是一种变构抑制剂，由Pleckstrin同源结构域激活。它能够抑制Akt的苏氨酸308位点和丝氨酸473位点的自身磷酸化，并阻止下游信号分子（包括TSC2、PRAS40及核糖体S6蛋白）的磷酸化。相较于抑制Ras突变型细胞系（如NCI-H358, NCI-H23, NCI-H1299, 和Calu-6），MK-2206更有效地抑制Ras野生型细胞系（如A431, HCC827, 和NCI-H292）。此外，与细胞毒素药剂如厄洛替尼和拉帕替尼联合使用于肺部NCI-H460肿瘤细胞或卵巢癌A2780肿瘤细胞时，MK-2206显示出协同效应。

体内研究

在用于NCI-H292移植瘤的治疗中，MK-2206表现出显著的抗癌活性。按动物体重，每千克处理240 mg MK-2206后，可抑制70%以上的Akt1/2在苏氨酸308位点和丝氨酸473位点的磷酸化，导致肿瘤生长抑制率达到60%，特别是在卵巢癌A2780移植瘤中。

文献信息

• TREATMENT OF OPHTHALMIC CONDITIONS SUCH AS MACULAR DEGENERATION, GLAUCOMA, AND DIABETIC RETINOPATHY USING PHARMACEUTICAL AGENTS THAT ELIMINATE SENESCENT CELLS
  申请人：Unity Biotechnology, Inc.

  公开号：EP3441069A1

  公开（公告）日：2019-02-13

  This invention is based on the discovery that many eye conditions associated with aging are mediated at least in part by cells bearing a senescent phenotype. Senescent cells accumulate with age, and express factors that contribute to the pathophysiology of age related conditions. The data show that in age-matched patients, the severity of age-related conditions correlates with the abundance of senescent cells, and that clearing senescent cells can help abrogate the condition. Small molecule drugs that remove senescent cells from affected tissue in the eye are provided as part of this invention that have special efficacy in treating ophthalmic conditions. They not only inhibit progression of the disease, they can also reverse some of the pathophysiology -such as neovascularization and vaso-obliteration -that lead to vision loss. These senolytic agents have an appropriate dose and specificity profile to be effective in the clinical management of previously intractable ophthalmic conditions.

  本发明基于以下发现：许多与衰老相关的眼部疾病至少部分是由具有衰老表型的细胞介导的。衰老细胞随着年龄的增长而积聚，并表达有助于老年相关疾病病理生理学的因子。数据显示，在年龄匹配的患者中，年龄相关疾病的严重程度与衰老细胞的数量相关，清除衰老细胞有助于缓解病情。作为本发明的一部分，本发明提供了可清除眼部受影响组织中衰老细胞的小分子药物，这些药物在治疗眼科疾病方面具有特殊疗效。它们不仅能抑制疾病的发展，还能逆转一些导致视力下降的病理生理学，如新生血管和血管闭塞。这些衰老溶解剂具有适当的剂量和特异性特征，可有效治疗以往难以治愈的眼科疾病。
• COMPOSITIONS FOR USE IN THE TREATMENT OF SENESCENCE-ASSIOCATED DISEASE AND DISORDERS
  申请人：Buck Institute for Research on Aging

  公开号：EP3669881A1

  公开（公告）日：2020-06-24

  Methods are provided herein for selectively killing senescent cells and for treating senescence-associated diseases and disorders by administering a senolytic agent. Senescence-associated diseases and disorders treatable by the methods using the senolytic agents described herein include cardiovascular diseases and disorders associated with or caused by arteriosclerosis, such as atherosclerosis; idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; osteoarthritis; senescence-associated ophthalmic diseases and disorders; and senescence-associated dermatological diseases and disorders.

  本文提供了选择性杀死衰老细胞和通过施用衰老分解剂治疗衰老相关疾病和紊乱的方法。可通过使用本文所述衰老分解剂的方法治疗的衰老相关疾病和失调包括与动脉硬化相关或由动脉硬化引起的心血管疾病和失调，如动脉粥样硬化；特发性肺纤维化；慢性阻塞性肺病；骨关节炎；衰老相关眼科疾病和失调；以及衰老相关皮肤病和失调。
• Polymeric nanoparticles and methods of making and using same
  申请人：Merck Sharp & Dohme Corp.

  公开号：US10022360B2

  公开（公告）日：2018-07-17

  Described herein are polymeric nanoparticles that comprise 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]-triazolo-[3,4-fJ[1,6]-naphthyridin-3-one (Compound A), or a pharmaceutically acceptable salt thereof, and methods of making and using such nanoparticles. The nanoparticle comprises about 50 to about 99.8 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer or a diblock poly(lactic acid-co-glycolic acid)-poly(ethylene)glycol copolymer, wherein the total amount of poly(ethylene)glycol in the nanoparticle is about 10 to about 30 weight percent poly(ethylene)glycol and about 0.2 to about 30 weight percent of Compound A.

  本文描述了包含 8-[4-(1-氨基环丁基)苯基]-9-苯基-2H-[1,2,4]-三唑-[3,4-fJ[1,6]-萘啶-3-酮（化合物 A）或其药学上可接受的盐的聚合物纳米粒子，以及制造和使用这种纳米粒子的方法。该纳米颗粒包含约50至约99.8重量％的二嵌段聚（乳酸）-聚（乙烯）二醇共聚物或二嵌段聚（乳酸-共-乙醇酸）-聚（乙烯）二醇共聚物，其中纳米颗粒中聚（乙烯）二醇的总量为约10至约30重量％的聚（乙烯）二醇和约0.2至约30重量％的化合物A。
• Treating atherosclerosis by removing senescent foam cell macrophages from atherosclerotic plaques
  申请人：Mayo Foundation for Medical Education and Research

  公开号：US10328058B2

  公开（公告）日：2019-06-25

  Foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines. In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease production. This invention provides methods and materials for treating arthritis by removing senescent cells in or around atherosclerotic plaques, thereby stabilizing the plaques, inhibiting rupture of the plaques and pathological sequelae that manifest as coronary artery disease.

  带有衰老标记的泡沫巨噬细胞在动脉粥样硬化开始时聚集在内皮下空间，它们通过增加主要致动脉粥样硬化和炎症细胞因子及趋化因子的表达来驱动病理变化。在晚期病变中，衰老细胞通过增加金属蛋白酶的产生，促进斑块的不稳定性特征，包括弹性纤维降解和纤维帽变薄。本发明提供了通过清除动脉粥样硬化斑块内或周围的衰老细胞来治疗关节炎的方法和材料，从而稳定斑块，抑制斑块破裂和表现为冠状动脉疾病的病理后遗症。
• Methods and compositions for killing senescent cells and for treating senescence-associated diseases and disorders using an inhibitor of Akt kinase
  申请人：Buck Institute for Research on Aging

  公开号：US10413542B2

  公开（公告）日：2019-09-17

  Methods are provided herein for selectively killing senescent cells and for treating senescence-associated diseases and disorders by administering a senolytic agent. Senescence-associated diseases and disorders treatable by the methods using the senolytic agents described herein include cardiovascular diseases and disorders associated with or caused by arteriosclerosis, such as atherosclerosis; idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; osteoarthritis; senescence-associated ophthalmic diseases and disorders; and senescence-associated dermatological diseases and disorders.

  本文提供了选择性杀死衰老细胞和通过施用衰老分解剂治疗衰老相关疾病和紊乱的方法。可通过使用本文所述衰老分解剂的方法治疗的衰老相关疾病和失调包括与动脉硬化相关或由动脉硬化引起的心血管疾病和失调，如动脉粥样硬化；特发性肺纤维化；慢性阻塞性肺病；骨关节炎；衰老相关眼科疾病和失调；以及衰老相关皮肤病和失调。