Design, synthesis, ADME and biological evaluation of benzylpiperidine and benzylpiperazine derivatives as novel reversible monoacylglycerol lipase (MAGL) inhibitors
Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved..
The degradation of the endocannabinoid 2-arachidonoylglycerol is mediated by the enzyme monoacylglycerol lipase (MAGL), thus generating arachidonic acid, the precursor of prostaglandins and other pro-inflammatory mediators. MAGL also contributes to the hydrolysis of monoacylglycerols into glycerol and fatty acids in peripheral body districts, which may act as pro-tumorigenic signals. For this reason, MAGL inhibitors have been considered as interesting therapeutic agents for their anti-nociceptive, anti-inflammatory, antioxidant and anti-cancer properties. So far, only a limited series of reversible MAGL inhibitors, which are devoid of side effects shown by irreversible inhibitors in animal models, have been reported. Here we optimized a class of benzylpiperidine and benzylpiperazine-based compounds for a reversible MAGL inhibition. The best MAGL inhibitors of this class, compounds 28 and 29, showed a very good inhibition potency, both on the isolated enzyme and in U937 cells, as confirmed by molecular modeling studies that predicted their binding mode into the MAGL active site. Both compounds are characterized by a high selectivity for MAGL versus other serine hydrolases including enzymes of the endocannabinoid system, as confirmed by ABPP experiments in mouse brain membranes. Moreover, very good properties concerning ADME parameters and low in vivo toxicity have been observed for both compounds.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 2023 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:263 |
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| Enthalten in: |
European journal of medicinal chemistry - 263(2023) vom: 05. Jan., Seite 115916 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Di Stefano, Miriana [VerfasserIn] |
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| Links: |
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| Themen: |
ADME |
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| Anmerkungen: |
Date Completed 04.12.2023 Date Revised 04.12.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2023.115916 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM364682434 |
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| 245 | 1 | 0 | |a Design, synthesis, ADME and biological evaluation of benzylpiperidine and benzylpiperazine derivatives as novel reversible monoacylglycerol lipase (MAGL) inhibitors |
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| 500 | |a published: Print-Electronic | ||
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| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved. | ||
| 520 | |a The degradation of the endocannabinoid 2-arachidonoylglycerol is mediated by the enzyme monoacylglycerol lipase (MAGL), thus generating arachidonic acid, the precursor of prostaglandins and other pro-inflammatory mediators. MAGL also contributes to the hydrolysis of monoacylglycerols into glycerol and fatty acids in peripheral body districts, which may act as pro-tumorigenic signals. For this reason, MAGL inhibitors have been considered as interesting therapeutic agents for their anti-nociceptive, anti-inflammatory, antioxidant and anti-cancer properties. So far, only a limited series of reversible MAGL inhibitors, which are devoid of side effects shown by irreversible inhibitors in animal models, have been reported. Here we optimized a class of benzylpiperidine and benzylpiperazine-based compounds for a reversible MAGL inhibition. The best MAGL inhibitors of this class, compounds 28 and 29, showed a very good inhibition potency, both on the isolated enzyme and in U937 cells, as confirmed by molecular modeling studies that predicted their binding mode into the MAGL active site. Both compounds are characterized by a high selectivity for MAGL versus other serine hydrolases including enzymes of the endocannabinoid system, as confirmed by ABPP experiments in mouse brain membranes. Moreover, very good properties concerning ADME parameters and low in vivo toxicity have been observed for both compounds | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ADME | |
| 650 | 4 | |a Benzylpiperazine | |
| 650 | 4 | |a Benzylpiperidine | |
| 650 | 4 | |a Inhibitors | |
| 650 | 4 | |a MAGL | |
| 650 | 4 | |a Monoacylglycerol lipase | |
| 650 | 7 | |a Monoacylglycerol Lipases |2 NLM | |
| 650 | 7 | |a EC 3.1.1.23 |2 NLM | |
| 650 | 7 | |a Monoglycerides |2 NLM | |
| 650 | 7 | |a Enzyme Inhibitors |2 NLM | |
| 650 | 7 | |a Endocannabinoids |2 NLM | |
| 700 | 1 | |a Masoni, Samuele |e verfasserin |4 aut | |
| 700 | 1 | |a Bononi, Giulia |e verfasserin |4 aut | |
| 700 | 1 | |a Poli, Giulio |e verfasserin |4 aut | |
| 700 | 1 | |a Galati, Salvatore |e verfasserin |4 aut | |
| 700 | 1 | |a Gado, Francesca |e verfasserin |4 aut | |
| 700 | 1 | |a Manzi, Simone |e verfasserin |4 aut | |
| 700 | 1 | |a Vagaggini, Chiara |e verfasserin |4 aut | |
| 700 | 1 | |a Brai, Annalaura |e verfasserin |4 aut | |
| 700 | 1 | |a Caligiuri, Isabella |e verfasserin |4 aut | |
| 700 | 1 | |a Asif, Kanwal |e verfasserin |4 aut | |
| 700 | 1 | |a Rizzolio, Flavio |e verfasserin |4 aut | |
| 700 | 1 | |a Macchia, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Chicca, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Sodi, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Di Bussolo, Valeria |e verfasserin |4 aut | |
| 700 | 1 | |a Minutolo, Filippo |e verfasserin |4 aut | |
| 700 | 1 | |a Meier, Philip |e verfasserin |4 aut | |
| 700 | 1 | |a Gertsch, Jürg |e verfasserin |4 aut | |
| 700 | 1 | |a Granchi, Carlotta |e verfasserin |4 aut | |
| 700 | 1 | |a Dreassi, Elena |e verfasserin |4 aut | |
| 700 | 1 | |a Tuccinardi, Tiziano |e verfasserin |4 aut | |
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