RESUMO
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).
Assuntos
Agonistas dos Receptores Histamínicos/uso terapêutico , Piperazina/química , Piperazinas/química , Receptores Histamínicos H3/metabolismo , Transtornos do Sono-Vigília/tratamento farmacológico , Animais , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Meia-Vida , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacocinética , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Piperazina/farmacocinética , Piperazina/uso terapêutico , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H3/química , Relação Estrutura-AtividadeRESUMO
Mutations in leucine-rich repeat kinase-2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD). The most frequent kinase-enhancing mutation is the G2019S residing in the kinase activation domain. This opens up a promising therapeutic avenue for drug discovery targeting the kinase activity of LRRK2 in PD. Several LRRK2 inhibitors have been reported to date. Here, we report a selective, brain penetrant LRRK2 inhibitor and demonstrate by a competition pulldown assay in vivo target engagement in mice.