2. Academic Validation
  3. Pyridin-2(1H)one derivatives: A possible new class of therapeutics for mechanical allodynia

Pyridin-2(1H)one derivatives: A possible new class of therapeutics for mechanical allodynia

  • Eur J Med Chem. 2020 Feb 1;187:111917. doi: 10.1016/j.ejmech.2019.111917.
Alexia Visseq 1,  Amélie Descheemaeker 2,  Nicolas Pinto-Pardo 2,  Lionel Nauton 1,  Vincent Théry 1,  Francis Giraud 1,  Isabelle Abrunhosa-Thomas 3,  Alain Artola 2,  Fabrice Anizon 4,  Radhouane Dallel 5,  Pascale Moreau 1
Affiliations

Affiliations

  • 1 Université Clermont Auvergne, CNRS, SIGMA Clermont, Institut de Chimie de Clermont-Ferrand, F-63000, Clermont-Ferrand, France.
  • 2 Université Clermont Auvergne, Inserm, Neuro-Dol, F-63000, Clermont-Ferrand, France.
  • 3 Université Clermont Auvergne, CNRS, SIGMA Clermont, Institut de Chimie de Clermont-Ferrand, F-63000, Clermont-Ferrand, France. Electronic address: [email protected].
  • 4 Université Clermont Auvergne, CNRS, SIGMA Clermont, Institut de Chimie de Clermont-Ferrand, F-63000, Clermont-Ferrand, France. Electronic address: [email protected].
  • 5 Université Clermont Auvergne, Inserm, Neuro-Dol, F-63000, Clermont-Ferrand, France; Centre Hospitalier Universitaire Clermont-Ferrand, Service D'Odontologie, F-63000, Clermont-Ferrand, France. Electronic address: [email protected].
PMID: 31806536 DOI: 10.1016/j.ejmech.2019.111917
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.

Keywords

Mechanical allodynia; Pyridin-2(1H)-ones; p38 MAPK.

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