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
The cataloguing of the human genome has provided an unprecedented prospectus for target identification and drug discovery. A current analysis indicates that slightly more than 3000 unique protein encoding loci are potentially amenable to pharmacological intervention (the 'druggable genome', which can be queried at http://function.gnf.org/druggable). However, the assessment of genome sequence data has not resulted in the anticipated acceleration of novel therapeutic developments. The basis for this shortfall lies in the significant attrition rates endemic to preclinical/clinical development, as well as the often underestimated complexity of gene function in higher order biological systems. To address the latter issue, a number of strategies have emerged to facilitate genomics-driven target identification and validation, including cellular profiling of gene function, in silico modelling of gene networks, and systematic analyses of protein complexes. The expectation is that the integration of these and other systems-based technologies may enable the conversion of potential genomic targets into functionally validated molecules, and result in practicable gene-based drug discovery pipelines.