Granchi Carlotta, Rizzolio Flavio, Palazzolo Stefano, Carmignani Sara, Macchia Marco, Saccomanni Giuseppe, Manera Clementina, Martinelli Adriano, Minutolo Filippo, Tuccinardi Tiziano
Department of Pharmacy, University of Pisa , Via Bonanno 6, 56126 Pisa, Italy.
Division of Experimental and Clinical Pharmacology, Department of Molecular Biology and Translational Research, National Cancer Institute and Center for Molecular Biomedicine, IRCCS , 33081 Aviano, Pordenone, Italy.
J Med Chem. 2016 Nov 23;59(22):10299-10314. doi: 10.1021/acs.jmedchem.6b01459. Epub 2016 Nov 14.
Monoacylglycerol lipase (MAGL) inhibitors are considered potential therapeutic agents for a variety of pathological conditions, including several types of cancer. Many MAGL inhibitors are reported in literature; however, most of them showed an irreversible mechanism of action, which caused important side effects. The use of reversible MAGL inhibitors has been only partially investigated so far, mainly because of the lack of compounds with good MAGL reversible inhibition properties. In this study, starting from the (4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone (CL6a) lead compound that showed a reversible mechanism of MAGL inhibition (K = 8.6 μM), we started its structural optimization and we developed a new potent and selective MAGL inhibitor (17b, K = 0.65 μM). Furthermore, modeling studies suggested that the binding interactions of this compound replace a structural water molecule reproducing its H-bonds in the MAGL binding site, thus identifying a new key anchoring point for the development of new MAGL inhibitors.
单酰甘油脂肪酶（MAGL）抑制剂被认为是治疗多种病理状况（包括几种类型的癌症）的潜在治疗药物。文献中报道了许多MAGL抑制剂；然而，它们中的大多数显示出不可逆的作用机制，这会导致重要的副作用。到目前为止，可逆MAGL抑制剂的使用仅得到了部分研究，主要是因为缺乏具有良好MAGL可逆抑制特性的化合物。在本研究中，从显示出可逆MAGL抑制机制（K = 8.6 μM）的（4-（4-氯苯甲酰基）哌啶-1-基）（4-甲氧基苯基）甲酮（CL6a）先导化合物开始，我们对其进行结构优化，并开发了一种新的强效且选择性的MAGL抑制剂（17b，K = 0.65 μM）。此外，建模研究表明，该化合物的结合相互作用取代了一个结构水分子，在MAGL结合位点重现了其氢键，从而为开发新的MAGL抑制剂确定了一个新的关键锚定点。
