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 anti-allodynic 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.

• Authors: Alexia Visseq, Amélie Descheemaeker, Karine Hérault, Francis Giraud, Isabelle Abrunhosa-Thomas, Alain Artola, Fabrice Anizon, Radhouane Dallel, Pascale Moreau
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 225 Pg. 113748 (Dec 05 2021) ISSN: 1768-3254 [Electronic] France
• PMID: 34392191 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Chemical References

• Analgesics
• Protein Kinase Inhibitors
• Pyridones
• Freund's Adjuvant
• p38 Mitogen-Activated Protein Kinases

Topics

• Analgesics (chemical synthesis, chemistry, pharmacology)
• Animals
• Freund's Adjuvant
• Hyperalgesia (drug therapy, metabolism)
• Molecular Structure
• Pain Measurement
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Pyridones (chemical synthesis, chemistry, pharmacology)
• Rats
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)