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Improved potency of pyridin-2(1H)one derivatives for the treatment of mechanical allodynia

Abstract : Mechanical allodynia, a painful sensation caused by innocuous touch, is a major chronic pain symptom, which often remains without an effective treatment. There is thus a need for new antiallodynic treatments based on new drug classes. We recently synthetized new 3,5-disubstituted pyridin-2(1H)-one derivatives. By substituting the pyridinone at the 3-position by various aryl/heteroaryl moieties and at the 5-position by a phenylamino group, we discovered that some derivatives exhibited a strong anti-allodynic potency in rats. Here, we report that varying the substitution of the pyridinone 5-position, the 3-position being substituted by an indol-4-yl moiety, further improves such anti-allodynic potency. Compared with 2, one of the two most active compounds of the first series, eleven out of nineteen newly synthetized compounds showed higher anti-allodynic potency, with two of them completely preventing mechanical allodynia. In the first series, hit compounds 1 and 2 appeared to be inhibitors of p38α MAPK, a protein kinase known to underlie pain hypersensitivity in animal models. Depending on the substitution at the 5-position, some newly synthetized compounds were also stronger p38α MAPK inhibitors. Surprisingly, though, anti-allodynic effects and p38α MAPK inhibitory potencies were not correlated, suggesting that other biological target(s) is/are involved in the analgesic activity in this series. Altogether, these results confirm that 3,5-disubstituted pyridine-2(1H)-one derivatives are of high interest for the development of new treatment of mechanical allodynia.
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Contributor : Fabrice Anizon Connect in order to contact the contributor
Submitted on : Friday, September 3, 2021 - 3:00:43 PM
Last modification on : Monday, September 6, 2021 - 11:55:27 AM

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Alexia Visseq, Amélie Descheemaeker, Karine Hérault, Francis Giraud, Isabelle Abrunhosa-Thomas, et al.. Improved potency of pyridin-2(1H)one derivatives for the treatment of mechanical allodynia. European Journal of Medicinal Chemistry, Elsevier, 2021, 225, pp.113748. ⟨10.1016/j.ejmech.2021.113748⟩. ⟨hal-03334145⟩

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