2-[[(苯甲酰基氨基)硫代甲酰]氨基]-4,7-二氢-5,5-二甲基-5H-噻吩并[2,3-C]吡喃-3-羧酸 | 314042-01-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并吡喃类
• 中文名称: 2-[[(苯甲酰基氨基)硫代甲酰]氨基]-4,7-二氢-5,5-二甲基-5H-噻吩并[2,3-C]吡喃-3-羧酸
• 英文名称: CID1067700
• 英文别名: 2-(3-benzoylthioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid；2-(benzoylcarbamothioylamino)-5,5-dimethyl-4,7-dihydrothieno[2,3-c]pyran-3-carboxylic acid
• CAS: 314042-01-8
• 化学式: C₁₈H₁₈N₂O₄S₂
• 分子量: 390.484
• InChiKey: ATSWBWHRHAQVFM-UHFFFAOYSA-N

物化性质

• 密度：
  1.410±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO：可溶10mg/mL，澄清

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  148
• 氢给体数：
  3
• 氢受体数：
  6

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

CID-1067700 (ML282) 是一种泛GTPase抑制剂，能够以竞争性方式抑制大脑 7 (Rab7)，Ki 值为 13 nM。

靶点

• Ki: 13 nM (Rab7)

体外研究

CID-1067700 (ML282) 是一种泛GTPase抑制剂，能以竞争性方式抑制 Rab7，Ki 值为 13 nM。它对 Rab7 的核苷结合显示出抑制活性，Kd值分别为 BODIPY-GTP 和 BODIPY-GDP 的 100 nM 和 40 nM。随着浓度增加，CID-1067700 强烈抑制了 BODIPY 连接的核苷酸结合，EC50 值分别为 BODIPY-GTP (11.22 ± 1.34 nM) 和 BODIPY-GDP (20.96 ± 1.34 nM)，计算得出的 Ki 值分别为 12.89 nM 和 19.70 nM。在等位结合条件下，CID-1067700 (10 μM) 对野生型 Rab7 释放绑定的 BODIPY 连接核苷酸没有影响。此外，在体外，CID-1067700 (0-40 μM) 能抑制 Rab7 活性、NF-κB 激活以及 B 细胞中的 AID 诱导，并通过靶向 Rab7 阻断 B 细胞中的类别转换 DNA 重排 (CSR)。

体内研究

在狼疮易感小鼠中，CID-1067700 (ML282; 16 mg/kg, i.p.) 能通过抑制 Rab7 来预防疾病的发展，并减少 MRL/Fas lpr/lpr 小鼠中的 IgG-IC 存积。CID-1067700 还靶向 B 细胞，特异性地损害体内的 CSR 机制。

文献信息

• Rab7 GTPase Inhibitors and Related Methods of Treatment
  申请人：Wandinger-Ness Angela

  公开号：US20140248268A1

  公开（公告）日：2014-09-04

  This invention relates to compounds and their use as inhibitors or activators of Rab7 GTPase to treat or prevent the onset of Rab 7 GTPase-associated disorders such as neuropathies, cancer, metabolic diseases of bone and lipid storage. The invention is also applicable to infectious diseases where Rab7 is inactivated or its protein-protein interactions are modulated to facilitate intracellular survival of pathogens. The compound described acts as a competitive inhibitor of nucleotide binding and as such also has utility as a scaffold for targeting other small GTPases. In one aspect, methods of treatment of the invention are used to treat or prevent the onset of hereditary sensory neuropathies such as Charcot-Marie-Tooth type 2B disease. Related pharmaceutical compositions, assays, and drug screens are also provided.

  本发明涉及化合物及其作为Rab7 GTP酶抑制剂或激活剂的用途，以治疗或预防Rab 7 GTP酶相关疾病，如神经病变、癌症、骨代谢疾病和脂质储存病。该发明还适用于Rab7被失活或其蛋白质-蛋白质相互作用被调节以促进病原体的细胞内生存的感染性疾病。所述化合物作为核苷酸结合的竞争性抑制剂，并且也具有作为靶向其他小GTP酶的支架的效用。在一个方面，本发明的治疗方法用于治疗或预防遗传性感觉神经病变，如Charcot-Marie-Tooth 2B病。还提供相关的制药组合物、测定和药物筛选。
• Treatment of autophagy-based disorders and related pharmaceutical compositions, diagnostic and screening assays and kits
  申请人：STC.UNM

  公开号：US10736910B2

  公开（公告）日：2020-08-11

  In one embodiment, the invention provides a method of treating a subject suffering from a Mycobacterium infection by administering to the subject a therapeutically-effective amount of a degradative autophagy agonist or a secretory autophagy antagonist. In another embodiment, the invention provides a method of treating a subject suffering from one or more diseases selected from the group consisting of a Mycobacterium infection, an inflammatory disorder, an immune disorder, a cancer and a neurodegenerative disorder by administering to the subject a therapeutically-effective amount of a TBK-1 antagonist (e.g. BX795 or amlexanox). Related pharmaceutical compositions, diagnostic and screening assays and kits are also provided.

  在一个实施方案中，本发明提供了一种治疗分枝杆菌感染受试者的方法，向受试者施用治疗有效量的降解型自噬激动剂或分泌型自噬拮抗剂。在另一个实施方案中，本发明提供了一种治疗患有一种或多种疾病的受试者的方法，这些疾病选自由分枝杆菌感染、炎症性疾病、免疫性疾病、癌症和神经退行性疾病组成的组，向受试者施用治疗有效量的 TBK-1 拮抗剂（如 BX795 或 amlexanox）。还提供了相关的药物组合物、诊断和筛选测定及试剂盒。
• Ras protein degradation inducing molecule and pharmaceutical composition
  申请人：Tokyo University of Science Foundation

  公开号：US11052154B2

  公开（公告）日：2021-07-06

  A Ras protein degradation inducing molecule that can induce degradation of Ras proteins, and a pharmaceutical composition that contains this Ras protein degradation inducing molecule are provided. The Ras protein degradation inducing molecule is a conjugate of a Ras protein affinity molecule which has affinity to Ras proteins, and a proteolysis-inducing tag which has affinity to protease and does not inhibit proteolysis of proteins by the protease.

  本发明提供了一种可诱导 Ras 蛋白降解的 Ras 蛋白降解诱导分子，以及一种含有这种 Ras 蛋白降解诱导分子的药物组合物。Ras 蛋白降解诱导分子是与 Ras 蛋白亲和的 Ras 蛋白亲和分子和与蛋白酶亲和的蛋白水解诱导标签的共轭物，蛋白水解诱导标签不抑制蛋白酶对蛋白质的蛋白水解。
• TREATMENT OF AUTOPHAGY-BASED DISORDERS AND RELATED PHARMACEUTICAL COMPOSITIONS, DIAGNOSTIC AND SCREENING ASSAYS AND KITS
  申请人：DERETIC Vojo P.

  公开号：US20150250808A1

  公开（公告）日：2015-09-10

  In one embodiment, the invention provides a method of treating a subject suffering from a Mycobacterium infection by administering to the subject a therapeutically-effective amount of a degradative autophagy agonist or a secretory autophagy antagonist. In another embodiment, the invention provides a method of treating a subject suffering from one or more diseases selected from the group consisting of a Mycobacterium infection, an inflammatory disorder, an immune disorder, a cancer and a neurodegenerative disorder by administering to the subject a therapeutically-effective amount of a TBK-1 antagonist (e.g. BX795 or amlexanox). Related pharmaceutical compositions, diagnostic and screening assays and kits are also provided.
• PROCESS FOR THE PREPARATION OF VENETOCLAX
  申请人：MYLAN LABORATORIES LIMITED

  公开号：US20190177317A1

  公开（公告）日：2019-06-13

  The present disclosure provides novel synthetic process for the preparation of venetoclax. The disclosed processes involve the use of novel intermediates. Processes for the preparation of these intermediates are also disclosed as well as methods for the preparation of particularly useful salts thereof.