12-(3-(金刚烷-1-基)脲基)十二酸 | 479413-70-2

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 中文名称: 12-(3-(金刚烷-1-基)脲基)十二酸
• 英文名称: 12-(3-adamantan-1-yl-ureido)dodecanoic acid
• 英文别名: 12‐(3‐adamantan‐1‐yl‐ureido)dodecanoic acid；12-[[(tricycle[3.3.1.1(3,7)]dec-1-ylamino)carbonyl]amino]dodecanoic acid；12-(((tricyclo(3.3.1.13,7)dec-1-ylamino)carbonyl)amino)-dodecanoic acid；12-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]dodecanoic acid；12-(3-adamantan-1-yl-ureido)dodecanoic acid butyl ester；12-(3-(adamantan-1-yl)ureido)dodecanoic acid；Auda；12-(1-adamantylcarbamoylamino)dodecanoic acid
• CAS: 479413-70-2
• 化学式: C₂₃H₄₀N₂O₃
• 分子量: 392.582
• InChiKey: XLGSEOAVLVTJDH-UHFFFAOYSA-N

物化性质

• 熔点：
  114 °C(Solv: hexane (110-54-3))
• 沸点：
  592.7±19.0 °C(Predicted)
• 密度：
  1.09±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：加热至60℃时≥10mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  28
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  78.4
• 氢给体数：
  3
• 氢受体数：
  3

安全信息

• 危险性防范说明：
  P264,P270,P301+P312,P330,P501
• 危险性描述：
  H302

制备方法与用途

生物活性

AUDA (化合物43) 是一种有效的水溶性环氧水解酶（sEH）抑制剂，对小鼠 sEH 和人 sEH 的 IC50 值分别为 18 nM 和 69 nM。AUDA 具有抗炎活性，可以降低 MMP-9、IL-1β、TNF-α 和 TGF-β 的水平，并下调 Smad3 和 p38 信号通路。

靶点

Target	Value
MMP-9
IL-1β
TNF-α
TGF-β
Smad3

体外研究

AUDA 在 0.3 至 10 μg/mL 浓度下，48 小时内剂量依赖性地抑制了 PDGF 暴露的小鼠血管平滑肌细胞 (VSMC) 的增殖；在 0.3 至 10 μg/mL 浓度下，30 分钟内剂量依赖性地上调 COX-2 表达；在 10、50 和 100 μM 浓度下剂量依赖性地增强了人脐静脉内皮细胞 (HCAECs) 的迁移能力，并显著提高了 HCAECs 的粘附能力。

细胞增殖实验

检测项
细胞系	VSMC
浓度 (μg/mL)	0.3, 1, 3, 10
孵育时间	48 小时
结果	剂量依赖性地抑制了 PDGF 暴露的小鼠 VSMC 的增殖

Western Blot 分析

检测项
细胞系	VSMC
浓度 (μg/mL)	1, 3, 10, 30
孵育时间	30 分钟
结果	剂量依赖性地上调 COX-2 表达

体内研究

AUDA 腹腔注射 (i.p.)，给药剂量为 10 mg/kg，持续 14 天后，降低了 TNF-α、MMP-9 和 IL-1β 的表达水平。

动物模型

检测项
动物模型	雄性野生型 C57BL/6 小鼠 (年龄 4-6 周，体重 18-20 g)
给药剂量	10 mg/kg
灌注途径	i.p.；14 天
结果	减少了 TNF-α、MMP-9 和 IL-1β 的表达水平

反应信息

• 作为反应物：
  描述：

  12-(3-(金刚烷-1-基)脲基)十二酸 在 lithium hydroxide 、 sodium methylate 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 12-(3-(1-adamantyl)ureido)dodecanoic acid [1-(2,3,4-trihydroxy-5-hydroxymethylcyclohexylcarbamoyl)nonyl]amide
  参考文献：
  名称：

  Design of bioavailable derivatives of 12-(3-adamantan-1-yl-ureido)dodecanoic acid, a potent inhibitor of the soluble epoxide hydrolase

  摘要：

  The soluble epoxide hydrolase (sEH) plays an important role in the metabolism of endogenous chemical mediators involved in blood pressure regulation and vascular inflammation. 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid (AUDA, 1) is a very active inhibitor of sEH both in vitro and in vivo. However, its relatively high melting point and limited solubility in either water or oil-based solvents leads to difficulties in formulating the compound and often results in poor in vivo availability. We investigated the effect of derivatization of the acid functional group of inhibitor I on the inhibition potencies, physical properties, and pharmacokinetic properties. For human sEH, similar inhibition potency was obtained when the acid of compound I was modified to esters (2-15). The resulting compounds exhibited improved physical properties (23-66 degrees C lower melting point and 5-fold better solubility in oil). Pharmacokinetic studies showed that the esters possess improved oral bioavailability in mice. On the other hand, amide derivatives of AUDA I did not show significant improvement in inhibition potencies or physical properties (higher melting points and lower solubility). The esterification of 1 results in compounds that are easier to formulate in animal food and in triglycerides for gavage and other routes of administration, making it easier to study the biological effects of sEH inhibition in vivo. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.09.057
• 作为产物：
  描述：

  异氰酸1-金刚烷酯 、 12-氨基十二酸 以 氯仿 为溶剂， 以2.66 g (100%)的产率得到12-(3-(金刚烷-1-基)脲基)十二酸
  参考文献：
  名称：

  Inhibitors for the soluble epoxide hydrolase

  摘要：

  提供了抑制可溶性环氧化酶（sEH）的抑制剂，这些抑制剂结合了多个药效团，在治疗疾病方面非常有用。

  公开号：

  US20050164951A1

文献信息

• DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160221965A1

  公开（公告）日：2016-08-04

  The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

  本申请涉及新颖的2,5-二取代6-(三氟甲基)嘧啶-4(3H)-酮衍生物，其制备方法，其单独或与其他药物联合用于治疗和/或预防疾病，以及用于制备治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
• POSITIVE ALLOSTERIC MODULATORS OF MUSCARINIC M2 RECEPTOR
  申请人：Bayer Pharma Aktiengesellschaft

  公开号：US20180297994A1

  公开（公告）日：2018-10-18

  The present application relates to positive allosteric modulators of the muscarinic M2 receptor, especially to novel 7-substituted 1-arylnaphthyridine-3-carboxamides, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prevention of diseases, and to the use thereof for production of medicaments for treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular disorders and/or renal disorders.

  本申请涉及肌动蛋白M2受体的阳性变构调节剂，特别是新型的7-取代的1-芳基萘啶-3-羧酰胺，以及其制备方法，单独或组合使用于治疗和/或预防疾病，以及用于生产治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管疾病和/或肾脏疾病。
• SUBSTITUTED IMIDAZOPYRIDINE AMIDES AND USE THEREOF
  申请人：Bayer Aktiengesellschaft

  公开号：US20200339567A1

  公开（公告）日：2020-10-29

  The present application relates to novel substituted imidazopyridine amides of the formula (I), to processes for their preparation, to their use, alone or in combinations, for the treatment and/or prophylaxis of diseases and to their use for the production of medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular, neurological and central nervous as well as metabolic disorders.

  本申请涉及新型取代咪唑吡啶酰胺的化合物（I）的制备方法，它们的使用，单独或组合用于治疗和/或预防疾病，以及它们用于生产用于治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、神经系统和中枢神经以及代谢紊乱疾病。
• SUBSTITUTED FUROPYRIMIDINES AND USE THEREOF
  申请人：Lampe Thomas

  公开号：US20110166163A1

  公开（公告）日：2011-07-07

  The present application relates to novel substituted furopyrimidine derivatives, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prophylaxis of cardiovascular diseases.

  本申请涉及新型的取代呋喃嘧啶衍生物，及其制备过程，用于治疗和/或预防疾病，以及用于制备用于治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管疾病。
• SUBSTITUTED N-BICYCLO-2-ARYL-QUINOLIN-4-CARBOXAMIDES AND USE THEREOF
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20180036300A1

  公开（公告）日：2018-02-08

  The present application relates to novel substituted N-bicyclo-2-arylquinoline-4-carboxamide derivatives, to processes for preparation thereof, to the use thereof alone or in combinations for treatment and/or prevention of diseases, and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially for treatment and/or prevention of fibrotic and inflammatory disorders.

  本申请涉及新型的取代N-双环[2.arylquinoline-4-carboxamide]衍生物，涉及其制备过程，涉及单独或联合使用该化合物治疗和/或预防疾病，以及涉及使用该化合物生产用于治疗和/或预防疾病的药物，特别用于治疗和/或预防纤维化和炎症性疾病。