TY - JOUR
T1 - Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor
AU - Granchi, Carlotta
AU - Lapillo, Margherita
AU - Glasmacher, Sandra
AU - Bononi, Giulia
AU - Licari, Cristina
AU - Poli, Giulio
AU - El Boustani, Maguie
AU - Caligiuri, Isabella
AU - Rizzolio, Flavio
AU - Gertsch, Jürg
AU - Macchia, Marco
AU - Minutolo, Filippo
AU - Tuccinardi, Tiziano
AU - Chicca, Andrea
PY - 2019/2/28
Y1 - 2019/2/28
N2 - Monoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arachidonoylglycerol, and it is involved in several physiological and pathological processes. The therapeutic potential of MAGL is linked to several diseases, including cancer. The development of MAGL inhibitors has been greatly limited by the side effects associated with the prolonged MAGL inactivation. Importantly, it could be preferable to use reversible MAGL inhibitors in vivo, but nowadays only few reversible compounds have been developed. In the present study, structural optimization of a previously developed class of MAGL inhibitors led to the identification of compound 23, which proved to be a very potent reversible MAGL inhibitor (IC 50 = 80 nM), selective for MAGL over the other main components of the endocannabinoid system, endowed of a promising antiproliferative activity in a series of cancer cell lines and able to block MAGL both in cell-based as well as in vivo assays.
AB - Monoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arachidonoylglycerol, and it is involved in several physiological and pathological processes. The therapeutic potential of MAGL is linked to several diseases, including cancer. The development of MAGL inhibitors has been greatly limited by the side effects associated with the prolonged MAGL inactivation. Importantly, it could be preferable to use reversible MAGL inhibitors in vivo, but nowadays only few reversible compounds have been developed. In the present study, structural optimization of a previously developed class of MAGL inhibitors led to the identification of compound 23, which proved to be a very potent reversible MAGL inhibitor (IC 50 = 80 nM), selective for MAGL over the other main components of the endocannabinoid system, endowed of a promising antiproliferative activity in a series of cancer cell lines and able to block MAGL both in cell-based as well as in vivo assays.
UR - http://www.scopus.com/inward/record.url?scp=85061920493&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061920493&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b01483
DO - 10.1021/acs.jmedchem.8b01483
M3 - Article
C2 - 30715876
AN - SCOPUS:85061920493
VL - 62
SP - 1932
EP - 1958
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 4
ER -