LCX001 | 1086378-73-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶二唑类
• 英文名称: LCX001
• 英文别名: N-(trans-4-hydroxycyclohexyl)-N-methylbenzo[c][1,2,5]oxadiazole-5-carboxamide；N-(trans-4-hydroxycyclohexyl)-N-methyl-2,1,3-benzoxadiazole-5-carboxamide
• CAS: 1086378-73-5
• 化学式: C₁₄H₁₇N₃O₃
• 分子量: 275.307
• InChiKey: RJSPKJWOSVQMSH-XYPYZODXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  20.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  79.46
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  LCX001 在 甲醇 、 偶氮二甲酸二异丙酯 、 叠氮磷酸二苯酯 、 sodium 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 反应 6.0h， 生成 N-(trans-4-azidocyclohexyl)-N-methyl-2,1,3-benzoxadiazole-5-carboxamide
  参考文献：
  名称：

  WO2008/143963

  摘要：

  公开号：
• 作为产物：
  描述：

  4-氨基-3-硝基苯甲酸 在 4-二甲氨基吡啶 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 potassium hydroxide 、 亚磷酸三乙酯 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 6.75h， 生成 LCX001
  参考文献：
  名称：

  WO2008/143963

  摘要：

  公开号：

文献信息

• Design, Synthesis and Biological Evaluation of Brain-Targeted Thiamine Disulfide Prodrugs of Ampakine Compound LCX001
  作者：Dian Xiao、Fan-Hua Meng、Wei Dai、Zheng Yong、Jin-Qiu Liu、Xin-Bo Zhou、Song Li

  DOI：10.3390/molecules21040488

  日期：——

  Ampakine compounds have been shown to reverse opiate-induced respiratory depression by activation of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. However, their pharmacological exploitations are hindered by low blood-brain barrier (BBB) permeability and limited brain distribution. Here, we explored whether thiamine disulfide prodrugs with the ability of “lock-in” can be used to solve these problems. A series of thiamine disulfide prodrugs 7a–7f of ampakine compound LCX001 was synthesized and evaluated. The trials in vitro showed that prodrugs 7e, 7d, 7f possessed a certain stability in plasma and quickly decomposed in brain homogenate by the disulfide reductase. In vivo, prodrug 7e decreased the peripheral distribution of LCX001 and significantly increased brain distribution of LCX001 after i.v. administration. This compound showed 2.23- and 3.29-fold greater increases in the AUC0-t and MRT0-t of LCX001 in brain, respectively, than did LCX001 itself. A preliminary pharmacodynamic study indicated that the required molar dose of prodrug 7e was only one eighth that of LCX001 required to achieve the same effect in mice. These findings provide an important reference to evaluate the clinical outlook of ampakine compounds.

  AMPakine化合物已被证明能够通过激活氨基-3-羟基-5-甲基-4-异噁唑丙酸（AMPA）谷氨酸受体来逆转阿片引起的呼吸抑制。然而，它们的药理应用受到低血脑屏障（BBB）通透性和有限脑内分布的阻碍。在此，我们探讨具有“锁定”能力的硫胺素二硫化物前药是否可以用来解决这些问题。我们合成并评估了一系列的硫胺素二硫化物前药7a–7f，该前药基于AMPakine化合物LCX001。体外试验表明，前药7e、7d、7f在血浆中具有一定稳定性，并在脑匀浆中快速被二硫化还原酶分解。在体内实验中，前药7e降低了LCX001的外周分布，并显著增加了LCX001在静脉给药后的脑内分布。与LCX001自身相比，该化合物在大脑中LCX001的AUC0-t和MRT0-t分别增加了2.23倍和3.29倍。初步的药效学研究表明，为实现同样效果，前药7e所需的摩尔剂量仅为LCX001的八分之一。这些发现为评估AMPakine化合物的临床前景提供了重要参考。
• AMPA受体增效剂的脑靶向前药及其医药用 途
  申请人：中国人民解放军军事医学科学院毒物药物研 究所

  公开号：CN107286114B

  公开（公告）日：2020-08-18

  本发明涉及通式I化合物，或其异构体、可药用盐及溶剂化物；本发明还涉及包含通式I化合物或其异构体、可药用盐及溶剂化物，以及药学上可接受的载体、赋形剂或稀释剂的组合物；本发明还涉及通式I化合物，或其异构体、可药用盐及溶剂化物，用于与谷氨酸功能低下的病症、神经退行性疾病、呼吸抑制的疾病或症状的用途；特别是用于与AMPA受体有关的疾病或症状中的用途。
• DI-SUBSTITUTED AMIDES FOR ENHANCING GLUTAMATERGIC SYNAPTIC RESPONSES
  申请人：Street Leslie

  公开号：US20120035173A1

  公开（公告）日：2012-02-09

  This invention relates to compounds, pharmaceutical compositions and methods for use in the prevention and treatment of cerebral insufficiency, including enhancement of receptor functioning in synapses in brain networks responsible for basic and higher order behaviors. These brain networks, which are involved in regulation of breathing, and cognitive abilities related to memory impairment, such as is observed in a variety of dementias, in imbalances in neuronal activity between different brain regions, as is suggested in disorders such as Parkinson's disease, schizophrenia, respiratory depression, sleep apneas, attention deficit hyperactivity disorder and affective or mood disorders, among numerous others. In a particular aspect, the invention relates to compounds useful for treatment of such conditions, and methods of using these compounds for such treatment.

  本发明涉及化合物、药物组合物及其在预防和治疗脑供血不足方面的应用方法，包括增强与基本和高级行为有关的脑网络中突触中受体功能。这些脑网络涉及呼吸调节和与记忆障碍相关的认知能力，例如在各种痴呆症中观察到的情况，以及在不同脑区域之间的神经活动失衡中所建议的帕金森病、精神分裂症、呼吸抑制、睡眠呼吸暂停、注意力缺陷多动障碍和情感或心境障碍等多种疾病。在一个特定的方面，本发明涉及用于治疗此类疾病的化合物，以及使用这些化合物进行此类治疗的方法。
• Di-Substituted Amides for Enhancing Glutamatergic Synaptic Responses
  申请人：Cortex Pharmaceuticals, Inc.

  公开号：US20130137733A1

  公开（公告）日：2013-05-30

  This invention relates to compounds, pharmaceutical compositions and methods for use in the prevention and treatment of cerebral insufficiency, including enhancement of receptor functioning in synapses in brain networks responsible for basic and higher order behaviors. These brain networks, which are involved in regulation of breathing, and cognitive abilities related to memory impairment, such as is observed in a variety of dementias, in imbalances in neuronal activity between different brain regions, as is suggested in disorders such as Parkinson's disease, schizophrenia, respiratory depression, sleep apneas, attention deficit hyperactivity disorder and affective or mood disorders, and in disorders wherein a deficiency in neurotrophic factors is implicated, as well as in disorders of respiration such as overdose of an alcohol, an opiate, an opioid, a barbiturate, an anesthetic, or a nerve toxin, or where the respiratory depression results form a medical condition such as central sleep apnea, stroke-induced central sleep apnea, obstructive sleep apnea, congenital hypoventilation syndrome, obesity hypoventilation syndrome, sudden infant death syndrome, Rett syndrome, spinal cord injury, traumatic brain injury, Cheney-Stokes respiration, Ondines curse, Prader-Willi's syndrome and drowning. In a particular aspect, the invention relates to compounds useful for treatment of such conditions, and methods of using these compounds for such treatment.

  本发明涉及化合物、制药组合物和用于预防和治疗脑供血不足的方法，包括增强大脑网络中负责基本和高级行为的突触中受体的功能。这些大脑网络涉及呼吸调节和与记忆障碍相关的认知能力，例如在多种痴呆症中观察到的情况，以及在不同脑区域之间的神经活动失衡中所建议的疾病，如帕金森病、精神分裂症、呼吸抑制、睡眠呼吸暂停、注意力缺陷多动症和情感或情绪障碍，以及神经营养因子缺乏所涉及的疾病，以及呼吸方面的疾病，例如酒精、鸦片、阿片类、巴比妥类、麻醉剂或神经毒素过量，或呼吸抑制由中枢性睡眠呼吸暂停、中风引起的中枢性睡眠呼吸暂停、阻塞性睡眠呼吸暂停、先天性低通气综合征、肥胖性低通气综合征、婴儿猝死综合征、雷特综合征、脊髓损伤、颅脑创伤、切尼-斯托克斯呼吸、昏迷和溺水等医疗状况引起。在特定方面，本发明涉及用于治疗这些疾病的化合物，以及使用这些化合物进行治疗的方法。
• Brain-targeting prodrug for AMPA receptor synergist, and pharmaceutical applications thereof
  申请人：Institute of Pharmacology and Toxicology Academy of Military Medical Sciences P.L.A. China

  公开号：US10759822B2

  公开（公告）日：2020-09-01

  Disclosed in the present invention is a compound of Formula (I), a geometric or optical isomer, a pharmaceutically acceptable salt, a solvate or a polymorph thereof. Also disclosed in the present invention is a composition comprising the compound of Formula (I), the geometric or optical isomer, the pharmaceutically acceptable salt, the solvate or the polymorph thereof. Also disclosed in the present invention is a use of the compound of Formula (I), the geometric or optical isomer, the pharmaceutically acceptable salt, the solvate or the polymorph thereof in the treatment of a disease or disorder such as a hypoglutamatergic condition, a neurodegenerative disease or respiratory depression, particularly in the treatment of a disease or disorder associated with AMPA receptor.

  本发明公开了式(I)化合物、几何或光学异构体、药学上可接受的盐、其溶解物或多晶型物。本发明还公开了一种包含式（I）化合物、几何或光学异构体、药学上可接受的盐、其溶液或其多晶型的组合物。本发明还公开了式(I)化合物、几何异构体或光学异构体、药学上可接受的盐、其溶解物或其多晶型在治疗疾病或紊乱中的用途，例如低谷氨酸症、神经退行性疾病或呼吸抑制，特别是在治疗与AMPA受体相关的疾病或紊乱中的用途。