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
Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.