哌嗪和哌啶甲酰胺及氨基甲酸酯类作为脂肪酸酰胺水解酶（FAAH）和单酰甘油脂肪酶（MAGL）的抑制剂。
Piperazine and piperidine carboxamides and carbamates as inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).
作者信息
Korhonen Jani, Kuusisto Anne, van Bruchem John, Patel Jayendra Z, Laitinen Tuomo, Navia-Paldanius Dina, Laitinen Jarmo T, Savinainen Juha R, Parkkari Teija, Nevalainen Tapio J
机构信息
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland.
School of Medicine, Institute of Biomedicine, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland.
出版信息
Bioorg Med Chem. 2014 Dec 1;22(23):6694-6705. doi: 10.1016/j.bmc.2014.09.012. Epub 2014 Sep 16.
The key hydrolytic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), are potential targets for various therapeutic applications. In this paper, we present more extensively the results of our previous work on piperazine and piperidine carboxamides and carbamates as FAAH and MAGL inhibitors. The best compounds of these series function as potent and selective MAGL/FAAH inhibitors or as dual FAAH/MAGL inhibitors at nanomolar concentrations. This study revealed that MAGL inhibitors should comprise leaving-groups with a conjugate acid pKa of 8-10, while diverse leaving groups are tolerated for FAAH inhibitors.
内源性大麻素系统的关键水解酶，脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL），是各种治疗应用的潜在靶点。在本文中，我们更广泛地展示了我们之前关于哌嗪和哌啶羧酰胺及氨基甲酸酯作为FAAH和MAGL抑制剂的研究结果。这些系列中最佳的化合物在纳摩尔浓度下作为强效和选择性的MAGL/FAAH抑制剂或双FAAH/MAGL抑制剂发挥作用。这项研究表明，MAGL抑制剂应包含共轭酸pKa为8 - 10的离去基团，而FAAH抑制剂则可耐受多种离去基团。
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