1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain.
1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain.
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DOI：
10.1021/jm100691c
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发表时间：
2010-10-14
影响因子：
7.3
通讯作者：
Hammock BD
中科院分区：
文献类型：
--
作者：
Rose TE;Morisseau C;Liu JY;Inceoglu B;Jones PD;Sanborn JR;Hammock BD
合成了一系列具有胡椒酰基片段的1,3-二取代脲类化合物，研究了它们作为人、鼠可溶性环氧化物水解酶（sEH）抑制剂的构效关系。小鼠口服13种1-芳基-3-（1-酰基哌啶-4-酰基）尿素抑制剂显示，与先前报道的1-金刚烷基尿素抑制剂相比，其药代动力学参数有实质性改善。例如，与金刚烷类似物1-（1-（环丙羰基）哌啶-4-基）-3-（4-（三氟甲氧基）苯基）尿素相比，1-（1-金刚烷基）-3-（1-丙基哌啶-4-基）尿素的效价增加了7倍，Cmax†增加了65倍，AUC增加了3300倍(2)。与吗啡相比，这种新型sEH抑制剂的效力增加了1000倍，通过使用体内卡拉胶诱导的炎症性疼痛模型，通过机械脱瘾阈值来减少痛觉过敏。
A series of 1,3-disubstituted ureas possessing a piperidyl moiety has been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine soluble epoxide hydrolase (sEH). Oral administration of thirteen 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantyl-urea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (52) showed a 7-fold increase in potency, a 65-fold increase in Cmax† and a 3300 fold increase in AUC over its adamantane analogue 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl)urea (2). This novel sEH inhibitor showed a 1000 fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mechanical withdrawl threshold using the in vivo carrageenan induced inflammatory pain model.
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影响因子：
5.7
作者：
Liu JY;Park SH;Morisseau C;Hwang SH;Hammock BD;Weiss RH
通讯作者：
Weiss RH
影响因子：
82.9
作者：
Moghaddam, MF;Grant, DF;Hammock, BD
通讯作者：
Hammock, BD
影响因子：
5
作者：
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影响因子：
2.7
作者：
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通讯作者：
Gless, Richard D.
影响因子：
3.6
作者：
DHAON, MK;OLSEN, RK;RAMASAMY, K
通讯作者：
RAMASAMY, K