RESUMEN
Histamine H3 receptor (H3R) inverse agonists that have been in clinical trials for the treatment of excessive sleep disorders, have been plagued with insomnia as a mechanism-based side effect. We focused on the identification of compounds that achieve high receptor occupancy within a short time, followed by rapid disengagement from the receptor, a target profile that could provide therapeutic benefits without the undesired side effect of insomnia. This article describes the optimization work that led to the discovery of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate (18 b, LML134).
Asunto(s)
Agonistas de los Receptores Histamínicos/uso terapéutico , Piperazina/química , Piperazinas/química , Receptores Histamínicos H3/metabolismo , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Animales , Evaluación Preclínica de Medicamentos , Agonismo Inverso de Drogas , Semivida , Agonistas de los Receptores Histamínicos/química , Agonistas de los Receptores Histamínicos/farmacocinética , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Piperazina/farmacocinética , Piperazina/uso terapéutico , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptores Histamínicos H3/química , Relación Estructura-ActividadRESUMEN
Voltage-gated sodium channels (Nav) are crucial to the initiation and propagation of action potentials (APs) in electrically excitable cells, and during the past decades they have received considerable attention due to their therapeutic potential. Here, we report for the first time the synthesis and the electrophysiological evaluation of 16 ligands based on a 2-methylbenzamide scaffold that have been identified as Nav1.1 modulators. Among these compounds, N,N'-(1,3-phenylene)bis(2-methylbenzamide) (3a) has been selected and evaluated in ex-vivo experiments in order to estimate the activation impact of such a compound profile. It appears that 3a increases the Nav1.1 channel activity although its overall impact remains moderate. Altogether, our preliminary results provide new insights into the development of small molecule activators targeting specifically Nav1.1 channels to design potential drugs for treating CNS diseases.