Pharmacological profiling of JME-173, a novel mexiletine derivative combining dual anti-inflammatory/anti-spasmodic functions and limited action in Na+ channels.

Abstract

Existing evidence suggests that the local anaesthetic mexiletine can be beneficial for patients with asthma. However, caution is required since anaesthesia of the airways inhibits protective bronchodilator neuronal reflexes, limiting applications in conditions of hyperirritable airways. Here, we describe the synthesis of a new series of mexiletine analogues, which were screened for reduced activity in Na+ channels and improved smooth muscle relaxant effects, that were evaluated using the patch-clamp technique and an isolated tracheal organ bath, respectively. JME-173 (1-(4-bromo-3,5-dimethylphenoxy)propan-2-amine) was the most effective among the four mexiletine analogues investigated. JME-173 was then studied in vivo using a murine model of lung inflammation induced by cigarette smoke (CS) and in vitro using neutrophil chemotaxis and mast cell degranulation assays. Finally, the JME-173 pharmacokinetic profile was assessed using HPLC-MS/MS bioanalytical method. JME-173 directly inhibited IL-8 (CXCL8)- and FMLP-induced human neutrophil chemotaxis and allergen-induced mast cell degranulation. After oral administration 1 h before CS exposure, JME-173 (50 mg/kg) strongly reduced the increased number of macrophages and neutrophils recovered in the bronchoalveolar effluent without altering lymphocyte counts. Pharmacokinetic experiments of JME-173 (10 mg/kg, orally) showed values of maximum concentration (Cmax), maximum time (Tmax), area under the blood concentration-time curve (AUC0-t) and area under the blood concentration-time curve from 0-Inf (AUC0-inf) of 163.3 ± 38.3 ng/mL, 1.2 ± 0.3 h, 729.4 ± 118.3 ng*h/ml and 868.9 ± 117.1 ng*h/ml (means ± S.E.M.), respectively. Collectively, these findings suggest that JME-173 has the potential to be an effective oral treatment for diseases associated with bronchoconstriction and inflammation.

• Authors: Douglas Pereira Pinto, Diego de Sá Coutinho, Katharinne Ingrid Moraes de Carvalho, Maximiliano R Ferrero, Letícia Vallim da Silva, Gabriel Parreiras Estolano Silveira, Diego Medeiros da Silva, João Felipe Garcia Araújo, Aline C A Silva, Heliana Martins Pereira, Laís Bastos da Fonseca, Robson Xavier Faria, Marcus Vinicius Nora de Souza, Emerson Teixeira da Silva, Osvaldo Andrade Santos-Filho, Jorge Carlos Santos da Costa, Fábio Coelho Amendoeira, Marco Aurélio Martins
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 885 Pg. 173367 (Oct 15 2020) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 32750364 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• JME-173
• Parasympatholytics
• Smoke
• Sodium Channel Blockers
• Sodium Channels
• Mexiletine

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Area Under Curve
• Bronchoalveolar Lavage Fluid (cytology)
• Cell Degranulation (drug effects)
• Humans
• Male
• Mast Cells (drug effects)
• Mexiletine (analogs & derivatives, pharmacology)
• Mice
• Neutrophil Infiltration (drug effects)
• Parasympatholytics (pharmacology)
• Patch-Clamp Techniques
• Pneumonia (chemically induced, drug therapy)
• Rats
• Rats, Wistar
• Smoke
• Sodium Channel Blockers (pharmacology)
• Sodium Channels (drug effects)
• Structure-Activity Relationship
• Tobacco Products