Article
Pharmacological profiling of JME-173, a novel mexiletine derivative combining dual anti-inflammatory/anti-spasmodic functions and limited action in Na+ channels
Registro en:
PINTO, Douglas Pereira et al. Pharmacological profiling of JME-173, a novel mexiletine derivative combining dual anti-inflammatory/anti-spamodic functions and limited action in Na+ channels. European Journal of Pharmacology, n. 885, 173367, p. 1-8, Aug. 2020.
0014-2999
10.1016/j.ejphar.2020.173367
0014-2999
Autor
Pinto, Douglas Pereira
Coutinho, Diego de Sá
Carvalho, Katharinne Ingrid Moares de
Ferrero, Maximiliano R.
Silva, Leticia Salim da
Silveira, Gabriel Parreiras Estolano
Silva, Diego Medeiros da
Araújo, João Felipe Garcia
Silva, Aline C. A.
Pereira, Heliana Martins
Fonseca, LaÍs Bastos da
Faria, Robson Xavier
Souza, Marcus Vinicius Nora de
Silva, Emerson Teixeira da
Santos Filho, Osvaldo Andrade
Costa, Jorge Carlos Santos da
Amendoeira, Fábio Coelho
Martins, Marco Aurélio
Resumen
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.