Identification of ABX-1431, a Selective Inhibitor of Monoacylglycerol Lipase and Clinical Candidate for Treatment of Neurological Disorders
Identification of ABX-1431, a Selective Inhibitor of Monoacylglycerol Lipase and Clinical Candidate for Treatment of Neurological Disorders
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DOI：
10.1021/acs.jmedchem.8b00951
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发表时间：
2018-10-25
影响因子：
7.3
通讯作者：
Grice, Cheryl A.
中科院分区：
文献类型：
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作者：
Cisar, Justin S.;Weber, Olivia D.;Grice, Cheryl A.
丝氨酸水解酶单酰基甘油脂肪酶（MGLL）将内源性大麻素受体激动剂2-花生四烯酸甘油（2-AG）和其它单酰基甘油转化为脂肪酸和甘油。MGLL的遗传或药理学失活导致中枢神经系统中2-AG的升高和花生四烯酸和类花生酸的相应减少，产生抗伤害感受、抗焦虑和抗神经炎性作用，而不诱导直接大麻素受体激动剂的全谱精神活性作用。在这里，我们报告了基于六氟异丙基氨基甲酸酯的MGLL不可逆抑制剂的优化，最终得到一种高效、选择性和口服的CNS渗透性MGLL抑制剂28（ABX-1431）。基于活性的蛋白质谱分析实验验证了28对MGLL相对于丝氨酸水解酶类的其他成员的精确选择性。在体内，28抑制啮齿动物脑中的MGLL活性（ED 50 = 0.5- 1.4mg/kg），增加脑2-AG浓度，并抑制大鼠福尔马林疼痛模型中的疼痛行为。ABX-1431（28）目前正在人体临床试验中进行评估。
The serine hydrolase monoacylglycerol lipase (MGLL) converts the endogenous cannabinoid receptor agonist 2-arachidonoylglycerol (2-AG) and other monoacylglycerols into fatty acids and glycerol. Genetic or pharmacological inactivation of MGLL leads to elevation in 2-AG in the central nervous system and corresponding reductions in arachidonic acid and eicosanoids, producing antinociceptive, anxiolytic, and antineuroinflammatory effects without inducing the full spectrum of psychoactive effects of direct cannabinoid receptor agonists. Here, we report the optimization of hexafluoroisopropyl carbamate-based irreversible inhibitors of MGLL, culminating in a highly potent, selective, and orally available, CNS-penetrant MGLL inhibitor, 28 (ABX-1431). Activity-based protein profiling experiments verify the exquisite selectivity of 28 for MGLL versus other members of the serine hydrolase class. In vivo, 28 inhibits MGLL activity in rodent brain (ED50 = 0.5-1.4 mg/kg), increases brain 2-AG concentrations, and suppresses pain behavior in the rat formalin pain model. ABX-1431 (28) is currently under evaluation in human clinical trials.