Development of terphenyl-2-methyloxazol-5(4H)-one derivatives as selective reversible MAGL inhibitors
Monoacylglycerol lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol. A wide number of MAGL inhibitors are reported in literature; however, many of them are characterised by an irreversible mechanism of action and thi...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2017-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/14756366.2017.1375484 |
| _version_ | 1818041706858151936 |
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| author | Carlotta Granchi Isabella Caligiuri Eleonora Bertelli Giulio Poli Flavio Rizzolio Marco Macchia Adriano Martinelli Filippo Minutolo Tiziano Tuccinardi |
| author_facet | Carlotta Granchi Isabella Caligiuri Eleonora Bertelli Giulio Poli Flavio Rizzolio Marco Macchia Adriano Martinelli Filippo Minutolo Tiziano Tuccinardi |
| author_sort | Carlotta Granchi |
| collection | DOAJ |
| description | Monoacylglycerol lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol. A wide number of MAGL inhibitors are reported in literature; however, many of them are characterised by an irreversible mechanism of action and this behavior determines an unwanted chronic MAGL inactivation, which acquires a functional antagonism of the endocannabinoid system. The possible use of reversible MAGL inhibitors has only recently been explored, due to the lack of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of terphenyl-2-methyloxazol-5(4H)-one derivatives characterised by a reversible MAGL-inhibition mechanism. Among them, compound 20b showed to be a potent MAGL reversible inhibitor (IC50 = 348 nM) with a good MAGL/FAAH selectivity. Furthermore, this compound showed antiproliferative activities against two different cancer cell lines that overexpress MAGL. |
| first_indexed | 2024-12-10T08:34:41Z |
| format | Article |
| id | doaj.art-6713ea22f79240ac81b20e055ca423c5 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-10T08:34:41Z |
| publishDate | 2017-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-6713ea22f79240ac81b20e055ca423c52022-12-22T01:56:00ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742017-01-013211240125210.1080/14756366.2017.13754841375484Development of terphenyl-2-methyloxazol-5(4H)-one derivatives as selective reversible MAGL inhibitorsCarlotta Granchi0Isabella Caligiuri1Eleonora Bertelli2Giulio Poli3Flavio Rizzolio4Marco Macchia5Adriano Martinelli6Filippo Minutolo7Tiziano Tuccinardi8University of PisaNational Cancer Institute and Center for Molecular BiomedicineUniversity of PisaUniversity of PisaCa’ Foscari Università di VeneziaUniversity of PisaUniversity of PisaUniversity of PisaUniversity of PisaMonoacylglycerol lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol. A wide number of MAGL inhibitors are reported in literature; however, many of them are characterised by an irreversible mechanism of action and this behavior determines an unwanted chronic MAGL inactivation, which acquires a functional antagonism of the endocannabinoid system. The possible use of reversible MAGL inhibitors has only recently been explored, due to the lack of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of terphenyl-2-methyloxazol-5(4H)-one derivatives characterised by a reversible MAGL-inhibition mechanism. Among them, compound 20b showed to be a potent MAGL reversible inhibitor (IC50 = 348 nM) with a good MAGL/FAAH selectivity. Furthermore, this compound showed antiproliferative activities against two different cancer cell lines that overexpress MAGL.http://dx.doi.org/10.1080/14756366.2017.1375484Monoacylglycerol lipase inhibitorsendocannabinoidsdockingmolecular dynamic simulations |
| spellingShingle | Carlotta Granchi Isabella Caligiuri Eleonora Bertelli Giulio Poli Flavio Rizzolio Marco Macchia Adriano Martinelli Filippo Minutolo Tiziano Tuccinardi Development of terphenyl-2-methyloxazol-5(4H)-one derivatives as selective reversible MAGL inhibitors Journal of Enzyme Inhibition and Medicinal Chemistry Monoacylglycerol lipase inhibitors endocannabinoids docking molecular dynamic simulations |
| title | Development of terphenyl-2-methyloxazol-5(4H)-one derivatives as selective reversible MAGL inhibitors |
| title_full | Development of terphenyl-2-methyloxazol-5(4H)-one derivatives as selective reversible MAGL inhibitors |
| title_fullStr | Development of terphenyl-2-methyloxazol-5(4H)-one derivatives as selective reversible MAGL inhibitors |
| title_full_unstemmed | Development of terphenyl-2-methyloxazol-5(4H)-one derivatives as selective reversible MAGL inhibitors |
| title_short | Development of terphenyl-2-methyloxazol-5(4H)-one derivatives as selective reversible MAGL inhibitors |
| title_sort | development of terphenyl 2 methyloxazol 5 4h one derivatives as selective reversible magl inhibitors |
| topic | Monoacylglycerol lipase inhibitors endocannabinoids docking molecular dynamic simulations |
| url | http://dx.doi.org/10.1080/14756366.2017.1375484 |
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