Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor.

Granchi, Carlotta; Lapillo, Margherita; Glasmacher, Sandra; Bononi, Giulia; Licari, Cristina; Poli, Giulio; El Boustani, Maguie; Caligiuri, Isabella; Rizzolio, Flavio; Gertsch, Jürg; Macchia, Marco; Minutolo, Filippo; Tuccinardi, Tiziano; Chicca, Andrea (2019). Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor. Journal of medicinal chemistry, 62(4), pp. 1932-1958. American Chemical Society 10.1021/acs.jmedchem.8b01483

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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 (IC50 = 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Glasmacher, Sandra Patricia; Gertsch, Jürg and Chicca, Andrea

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0022-2623

Publisher:

American Chemical Society

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

26 Sep 2019 14:54

Last Modified:

05 Nov 2019 08:24

Publisher DOI:

10.1021/acs.jmedchem.8b01483

PubMed ID:

30715876

BORIS DOI:

10.7892/boris.133494

URI:

https://boris.unibe.ch/id/eprint/133494

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