Abstract |
Mechanical Allodynia (MA), a frequent chronic pain symptom caused by innocuous stimuli, constitutes an unmet medical need, as treatments using analgesics available today are not always effective and can be associated with important side-effects. A series of 3,5-disubstituted pyridin-2(1H)-ones was designed, synthesized and evaluated in vivo toward a rat model of inflammatory MA. We found that the series rapidly and strongly prevented the development of MA. 3-(2-Bromophenyl)-5-(phenylamino)pyridin-2(1H)-one 69, the most active compound of the series, was also able to quickly reverse neuropathic MA in rats. Next, when 69 was evaluated toward a panel of 50 protein kinases (PK) in order to identify its potential biological target(s), we found that 69 is a p38α MAPK inhibitor, a PK known to contribute to pain hypersensitivity in animal models. 3,5-Disubstituted pyridin-2(1H)-ones thus could represent a novel class of analgesic for the treatment of MA.
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Authors | Alexia Visseq, Amélie Descheemaeker, Nicolas Pinto-Pardo, Lionel Nauton, Vincent Théry, Francis Giraud, Isabelle Abrunhosa-Thomas, Alain Artola, Fabrice Anizon, Radhouane Dallel, Pascale Moreau |
Journal | European journal of medicinal chemistry
(Eur J Med Chem)
Vol. 187
Pg. 111917
(Feb 01 2020)
ISSN: 1768-3254 [Electronic] France |
PMID | 31806536
(Publication Type: Journal Article)
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Copyright | Copyright © 2019 Elsevier Masson SAS. All rights reserved. |
Chemical References |
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Topics |
- Analgesics
(chemical synthesis, chemistry, therapeutic use)
- Animals
- Dose-Response Relationship, Drug
- Hyperalgesia
(drug therapy)
- Molecular Structure
- Pain Measurement
- Pyridones
(chemical synthesis, chemistry, therapeutic use)
- Rats
- Structure-Activity Relationship
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