TY - JOUR
T1 - Structural Optimization of 4-Chlorobenzoylpiperidine Derivatives for the Development of Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors
AU - Granchi, Carlotta
AU - Rizzolio, Flavio
AU - Palazzolo, Stefano
AU - Carmignani, Sara
AU - Macchia, Marco
AU - Saccomanni, Giuseppe
AU - Manera, Clementina
AU - Martinelli, Adriano
AU - Minutolo, Filippo
AU - Tuccinardi, Tiziano
PY - 2016/11/23
Y1 - 2016/11/23
N2 - 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 (Ki = 8.6 μM), we started its structural optimization and we developed a new potent and selective MAGL inhibitor (17b, Ki = 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.
AB - 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 (Ki = 8.6 μM), we started its structural optimization and we developed a new potent and selective MAGL inhibitor (17b, Ki = 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.
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U2 - 10.1021/acs.jmedchem.6b01459
DO - 10.1021/acs.jmedchem.6b01459
M3 - Article
AN - SCOPUS:84999099051
VL - 59
SP - 10299
EP - 10314
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 22
ER -