Abstract
Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays an important role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol, which is implicated in many physiological processes. Beyond the possible utilization of MAGL inhibitors as anti-inflammatory, antinociceptive, and anticancer agents, their application has encountered obstacles due to the unwanted effects caused by the irreversible inhibition of this enzyme. The possible application of reversible MAGL inhibitors has only recently been explored, mainly due to the deficiency of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of reversible MAGL inhibitors. Among them, compound 26 showed to be a potent MAGL inhibitor (IC50 = 0.51 μM, Ki = 412 nM) with a good selectivity versus fatty acid amide hydrolase (FAAH), α/β-hydrolase domain-containing 6 (ABHD6), and 12 (ABHD12). Interestingly, this compound also possesses antiproliferative activities against two different cancer cell lines and relieves the neuropathic hypersensitivity induced in vivo by oxaliplatin.
| Original language | English |
|---|---|
| Pages (from-to) | 1340-1354 |
| Number of pages | 15 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 61 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Feb 8 2018 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
Discovery of 1,5-Diphenylpyrazole-3-Carboxamide Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors. / Aghazadeh Tabrizi, Mojgan; Baraldi, Pier Giovanni; Baraldi, Stefania; Ruggiero, Emanuela; De Stefano, Lucia; Rizzolio, Flavio; Di Cesare Mannelli, Lorenzo; Ghelardini, Carla; Chicca, Andrea; Lapillo, Margherita; Gertsch, Jürg; Manera, Clementina; Macchia, Marco; Martinelli, Adriano; Granchi, Carlotta; Minutolo, Filippo; Tuccinardi, Tiziano.
In: Journal of Medicinal Chemistry, Vol. 61, No. 3, 08.02.2018, p. 1340-1354.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Discovery of 1,5-Diphenylpyrazole-3-Carboxamide Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors
AU - Aghazadeh Tabrizi, Mojgan
AU - Baraldi, Pier Giovanni
AU - Baraldi, Stefania
AU - Ruggiero, Emanuela
AU - De Stefano, Lucia
AU - Rizzolio, Flavio
AU - Di Cesare Mannelli, Lorenzo
AU - Ghelardini, Carla
AU - Chicca, Andrea
AU - Lapillo, Margherita
AU - Gertsch, Jürg
AU - Manera, Clementina
AU - Macchia, Marco
AU - Martinelli, Adriano
AU - Granchi, Carlotta
AU - Minutolo, Filippo
AU - Tuccinardi, Tiziano
PY - 2018/2/8
Y1 - 2018/2/8
N2 - Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays an important role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol, which is implicated in many physiological processes. Beyond the possible utilization of MAGL inhibitors as anti-inflammatory, antinociceptive, and anticancer agents, their application has encountered obstacles due to the unwanted effects caused by the irreversible inhibition of this enzyme. The possible application of reversible MAGL inhibitors has only recently been explored, mainly due to the deficiency of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of reversible MAGL inhibitors. Among them, compound 26 showed to be a potent MAGL inhibitor (IC50 = 0.51 μM, Ki = 412 nM) with a good selectivity versus fatty acid amide hydrolase (FAAH), α/β-hydrolase domain-containing 6 (ABHD6), and 12 (ABHD12). Interestingly, this compound also possesses antiproliferative activities against two different cancer cell lines and relieves the neuropathic hypersensitivity induced in vivo by oxaliplatin.
AB - Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays an important role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol, which is implicated in many physiological processes. Beyond the possible utilization of MAGL inhibitors as anti-inflammatory, antinociceptive, and anticancer agents, their application has encountered obstacles due to the unwanted effects caused by the irreversible inhibition of this enzyme. The possible application of reversible MAGL inhibitors has only recently been explored, mainly due to the deficiency of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of reversible MAGL inhibitors. Among them, compound 26 showed to be a potent MAGL inhibitor (IC50 = 0.51 μM, Ki = 412 nM) with a good selectivity versus fatty acid amide hydrolase (FAAH), α/β-hydrolase domain-containing 6 (ABHD6), and 12 (ABHD12). Interestingly, this compound also possesses antiproliferative activities against two different cancer cell lines and relieves the neuropathic hypersensitivity induced in vivo by oxaliplatin.
UR - http://www.scopus.com/inward/record.url?scp=85041903551&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041903551&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.7b01845
DO - 10.1021/acs.jmedchem.7b01845
M3 - Article
AN - SCOPUS:85041903551
VL - 61
SP - 1340
EP - 1354
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 3
ER -