环戊乙酸,3-氨基-3-羧基-,反-(9CI) | 192755-52-5

• 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
• 中文名称: 环戊乙酸,3-氨基-3-羧基-,反-(9CI)
• 中文别名: (1S,9S)-N-[(2R,3S)-2-乙氧基-5-氧代四氢呋喃-3-基]-9-(异喹啉-1-羰基氨基)-6,10-二氧代-2,3,4,7,8,9-六氢-1H-哒嗪并[1,2-a]二氮杂卓-1-甲酰胺
• 英文名称: Pralnacasan
• 英文别名: (4S,7S)-N-[(2R,3S)-2-ethoxy-5-oxooxolan-3-yl]-7-(isoquinoline-1-carbonylamino)-6,10-dioxo-2,3,4,7,8,9-hexahydro-1H-pyridazino[1,2-a]diazepine-4-carboxamide
• CAS: 192755-52-5
• 化学式: C₂₆H₂₉N₅O₇
• 分子量: 523.5
• InChiKey: CXAGHAZMQSCAKJ-WAHHBDPQSA-N

物化性质

• 密度：
  1.44±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  38
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  147
• 氢给体数：
  2
• 氢受体数：
  8

ADMET

毒理性

• 药物性肝损伤

pralnacasan

Compound:pralnacasan

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：已停产

Label Section:Discontinued

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服生物利用度高

Orally bioavailable

来源:DrugBank

制备方法与用途

生物活性

Pralnacasan (VX-740) 是一种有效的、选择性的非肽型，具有口服活性的白介素 1β 转化酶 (ICE, caspase 1) 抑制剂，其 Ki 值为 1.4 nM。这种抑制剂能够有效抑制促炎细胞因子 IL-18、IL-1β 和 IFN-γ 的生成。Pralnacasan 有望用于骨关节炎和类风湿关节炎的研究。

靶点

• 靶标名称: 白介素-1β 转化酶
• Ki 值: 1.4 nM

体内研究

在实验中，Pralnacasan (0 -50 mg/kg；口服灌胃；每日两次；持续6周；雌性Balb/c小鼠) 的治疗显著减轻了关节损伤。动物的体重未见明显变化。

实验参数	参数值
动物模型	雌性Balb/c小鼠诱导胶原酶注射
剂量	0 mg/kg，12.5 mg/kg，25 mg/kg 和 50 mg/kg
给药方式	口服灌胃；每日两次；持续6周
结果	显著改善了内侧膝关节腔的组织病理学损伤。

文献信息

• Hydroxylated nebivolol metabolites
  申请人：O'Donnell P. John

  公开号：US20070014733A1

  公开（公告）日：2007-01-18

  Hydroxylated nebivolol metabolites increase NO release from human endothelial cell preparations in a concentration dependent fashion following acute administration. In addition, hydroxylated nebivolol metabolites, including but not limited to 4-hydroxy-6,6′difluoro-, 4-hydroxy-5-phenol-6,6′difluoro-, and 4-hydroxy-8-pheno-6,6′difluoro-, have the ability to increase the capacity for NO release in human endothelial cells following chronic administration. This invention provides hydroxylated nebivolol metabolites and compositions comprising nebivolol and/or at least one hydroxylated metabolite of nebivolol and/or at least one additional compound used to treat cardiovascular diseases or a pharmaceutically acceptable salt thereof. In addition, this invention provides methods of treating and/or preventing vascular diseases by administering at least one hydroxylated metabolite of nebivolol that is capable of releasing a therapeutically effective amount of nitric oxide to a targeted site affected by the vascular disease. Also, this invention is directed to the treatment and/or prevention of migraine headaches administering at least one hydroxylated metabolite of nebivolol. This invention may also be used in conjunction with or as a single treatment of metabolic syndrome disorders.

  羟基化奈必洛尔代谢物在急性给药后以浓度依赖性方式增加人内皮细胞制剂的一氧化氮释放。此外，羟基化奈必洛尔代谢物，包括但不限于4-羟基-6,6'-二氟代-、4-羟基-5-苯酚-6,6'-二氟代-和4-羟基-8-苯并-6,6'-二氟代-，在慢性给药后能够增加人内皮细胞的一氧化氮释放能力。本发明提供了羟基化奈必洛尔代谢物和包含奈必洛尔和/或至少一种羟基化奈必洛尔代谢物和/或至少一种用于治疗心血管疾病的附加化合物的组合物，以及可药用的盐。此外，本发明还提供了通过给药至少一种能够释放治疗有效量的一氧化氮到受血管疾病影响的靶向部位的羟基化奈必洛尔代谢物来治疗和/或预防血管疾病的方法。本发明还涉及通过给药至少一种羟基化奈必洛尔代谢物来治疗和/或预防偏头痛。本发明还可以与治疗代谢综合征障碍的其他治疗联合使用，或作为单一治疗。
• [EN] SYNTHESIS OF RESORCYLIC ACID LACTONES USEFUL AS THERAPEUTIC AGENTS<br/>[FR] SYNTHÈSE DE LACTONES D'ACIDE RÉSORCYLIQUE UTILES EN TANT QU'AGENTS THÉRAPEUTIQUES
  申请人：UNIV STRASBOURG

  公开号：WO2009091921A1

  公开（公告）日：2009-07-23

  Disclosed are macrocyclic compounds of formulae I, I', II, II', III, III', IV, and V, which are analogs of the pochonin resorcylic acid lactones, pharmaceutical compositions comprising the compounds, and methods and uses comprising the compounds for the treatment of diseases mediated by kinases and Heat Shock Protein 90 HSP90.

  公开的是式I、I'、II、II'、III、III'、IV和V的大环化合物，它们是pochonin resorcylic acid lactones的类似物，包括这些化合物的药物组合物，以及包括这些化合物用于治疗由激酶和热休克蛋白90 HSP90介导的疾病的方法和用途。
• [EN] NEW CCR2 RECEPTOR ANTAGONISTS AND USES THEREOF<br/>[FR] NOUVEAUX ANTAGONISTES DU RÉCEPTEUR CCR2 ET LEURS UTILISATIONS
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2011073154A1

  公开（公告）日：2011-06-23

  The present invention relates to novel antagonists for CCR2 (CC chemokine receptor 2) of Formula (I) and their use for providing medicaments for treating conditions and diseases, especially pulmonary diseases like asthma and COPD.

  本发明涉及一种新型CCR2（CC趋化因子受体2）拮抗剂的化学式（I），以及它们用于提供治疗疾病和病症的药物，特别是肺部疾病如哮喘和慢性阻塞性肺病。
• NEW CCR2 RECEPTOR ANTAGONISTS AND USES THEREOF
  申请人：Ebel Heiner

  公开号：US20120004252A1

  公开（公告）日：2012-01-05

  The present invention relates to novel antagonists for CCR2 (CC chemokine receptor 2) and their use for providing medicaments for treating conditions and diseases, especially pulmonary diseases like asthma and COPD.

  本发明涉及用于治疗疾病和疾病的新型CCR2（CC趋化因子受体2）拮抗剂及其用途，特别是用于治疗哮喘和慢性阻塞性肺病等肺部疾病的药物。
• [EN] NOVEL AND SELECTIVE CCR2 ANTAGONISTS<br/>[FR] ANTAGONISTES DE CCR2 NOUVEAUX ET SÉLECTIFS
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2013010839A1

  公开（公告）日：2013-01-24

  The present invention relates to novel and selective antagonists for CCR2 (CC chemokine receptor 2) and their use for providing medicaments for treating conditions and diseases, especially pulmonary diseases like asthma and COPD as well as pain. Claimed are compounds of formula (I), wherein G and E are independently selected from among C-H or N; wherein A is a group selected from among wherein R6 is a group of the structure -L1-R13, wherein L1 is selected from among -NH-, and -N(C1-C4-alkyl)-, and wherein R13 is selected from among -C5-C6-heterocyclyl comprising 1 or 2 hetero atoms selected from among N, and 0, and wherein R13 is optionally substituted; The other variables are as defined in the claims

  本发明涉及用于治疗疾病和病症的新型和选择性CCR2（CC趋化因子受体2）拮抗剂，特别是用于治疗哮喘、COPD以及疼痛等肺部疾病的药物。所述的化合物具有以下结构（I）中的公式，其中G和E分别选自C-H或N；A是从中选择的一个基团，其中R6是结构-L1-R13的一个基团，其中L1从-NH-和-N（C1-C4-烷基）中选择，R13从包含1或2个异原子（N和0中选择）的-C5-C6-杂环烷基中选择，并且R13可选择性地被取代；其他变量如权利要求中所定义。