Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity
Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity
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DOI：
10.1021/bi701378g
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发表时间：
2007-11-13
期刊：
影响因子：
2.9
通讯作者：
Cravatt, Benjamin F.
中科院分区：
文献类型：
--
作者：
Ahn, Kyunghye;Johnson, Douglas S.;Cravatt, Benjamin F.
脂肪酸酰胺水解酶（FAAH）是一种完整的膜酶，可降解信号脂质的脂肪酸酰胺家族，包括内源性大麻素anandamide。遗传或药理学上FAAH的失活导致啮齿类动物的镇痛、抗炎、抗焦虑和抗抑郁表型，而不显示直接大麻素受体激动剂所观察到的不良副作用，这表明FAAH可能是治疗疼痛、炎症和其他中枢神经系统疾病的有吸引力的治疗靶点。然而，迄今为止报道的FAAH抑制剂缺乏药物样药代动力学性质和/或选择性。本文将以n-苯基-4-（喹啉-3-基甲基）哌啶-1-羧酰胺（PF-750）和n-苯基-4-（喹啉-2-基甲基）哌啶-1-羧酰胺（PF-622）为代表的哌啶/哌嗪脲类描述为一类新的FAAH抑制剂。PF-750和PF-622显示出比先前建立的FAAH抑制剂更高的体外效力。出乎意料的是，基于尿素官能团的高化学稳定性，PF-750和PF-622通过共价修饰酶的活性位点丝氨酸亲核试剂，以时间依赖性的方式抑制FAAH。基于活性的蛋白质组学分析显示，相对于其他哺乳动物丝氨酸水解酶，PF-750和PF-622对FAAH具有完全的选择性。我们推测，这种显著的特异性至少部分源于FAAH作为C(O)-N键水解酶的特殊功能，这将其与哺乳动物中绝大多数仅限于水解酯和/或硫酯的代谢性丝氨酸水解酶区分开来。因此，哌啶/哌嗪尿素可能代表了一种特殊的化学支架，用于合成FAAH抑制剂，这些抑制剂显示出前所未有的效力和选择性，可作为潜在的镇痛药和抗焦虑药/抗抑郁药。
Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or phannacological inactivation of FAAH leads to analgesic, anti-inflammatory, anxiolytic, and antidepressant phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for treatment of pain, inflammation, and other central nervous system disorders. However, the FAAH inhibitors reported to date lack drug-like pharmacokinetic properties and/or selectivity. Herein we describe piperidine/piperazine ureas represented by N-phenyl-4-(quinolin-3-ylmethyl)piperidine-1-carboxamide (PF-750) and N-phenyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide (PF-622) as a novel mechanistic class of FAAH inhibitors. PF-750 and PF-622 show higher in vitro potencies than previously established classes of FAAH inhibitors. Rather unexpectedly based on the high chemical stability of the urea functional group, PF-750 and PF-622 were found to inhibit FAAH in a time-dependent manner by covalently modifying the enzyme's active site serine nucleophile. Activity-based proteomic profiling revealed that PF-750 and PF-622 were completely selective for FAAH relative to other mammalian serine hydrolases. We hypothesize that this remarkable specificity derives, at least in part, from FAAH's special ability to function as a C(O)-N bond hydrolase, which distinguishes it from the vast majority of metabolic serine hydrolases in mammals that are restricted to hydrolyzing esters and/or thioesters. The piperidine/piperazine urea may thus represent a privileged chemical scaffold for the synthesis of FAAH inhibitors that display an unprecedented combination of potency and selectivity for use as potential analgesic and anxiolytic/antidepressant agents.