RESUMO
Aggregates of tau and beta amyloid (Aß) plaques constitute the histopathological hallmarks of Alzheimer's disease and are prominent targets for novel therapeutics as well as for biomarkers for diagnostic in vivo imaging. In recent years much attention has been devoted to the discovery and development of new PET tracers to image tau aggregates in the living human brain. Access to a selective PET tracer to image and quantify tau aggregates represents a unique tool to support the development of any novel therapeutic agent targeting pathological forms of tau. The objective of the study described herein was to identify such a novel radiotracer. As a result of this work, we discovered three novel PET tracers (2-(4-[11C]methoxyphenyl)imidazo[1,2-a]pyridin-7-amine 7 ([11C]RO6924963), N-[11C]methyl-2-(3-methylphenyl)imidazo[1,2-a]pyrimidin-7-amine 8 ([11C]RO6931643), and [18F]2-(6-fluoropyridin-3-yl)pyrrolo[2,3-b:4,5-c']dipyridine 9 ([18F]RO6958948)) with high affinity for tau neurofibrillary tangles, excellent selectivity against Aß plaques, and appropriate pharmacokinetic and metabolic properties in mice and non-human primates.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Radioisótopos de Carbono/química , Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons/métodos , Agregação Patológica de Proteínas/diagnóstico por imagem , Pirimidinas/química , Proteínas tau/análise , Animais , Radioisótopos de Carbono/farmacocinética , Radioisótopos de Flúor/farmacocinética , Humanos , Masculino , Camundongos , Papio , Pirimidinas/farmacocinéticaRESUMO
During a program directed at selective NK(1) receptor antagonists, we serendipitously discovered an NK(1) receptor ligand with additional affinity for the NK(3) receptor. Recognising an opportunity for a drug discovery program aiming for dual NK(1)/NK(3) receptor antagonists, we prepared a series of analogues from a novel, versatile building block. From this series emerged compounds with high and balanced affinities for the NK(1) and the NK(3) receptors. Typical representatives of this series were active in the gerbil foot tapping assay after oral administration.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-3/antagonistas & inibidores , Administração Oral , Animais , Descoberta de Drogas , Ligantes , Modelos Moleculares , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-3/metabolismoRESUMO
Lead optimisation of the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine class led to the identification of two clinical leads [RO4882224 (11) and RO4938581 (44)] functioning as novel potent and selective GABAA alpha5 inverse agonists. The unique pharmacological profiles and optimal pharmacokinetic profiles resulted in in vivo activity in selected cognition models.
Assuntos
Anticonvulsivantes/farmacocinética , Benzodiazepinas/farmacocinética , Transtornos Cognitivos/tratamento farmacológico , Imidazóis/farmacocinética , Receptores de GABA-A/metabolismo , Triazóis/farmacocinética , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Linhagem Celular , Modelos Animais de Doenças , Descoberta de Drogas , Agonismo Inverso de Drogas , Agonistas de Receptores de GABA-A , Humanos , Imidazóis/síntese química , Imidazóis/química , Camundongos , Ligação Proteica , Ratos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
Through iterative design cycles we have discovered a number of novel new classes where the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine was deemed the most promising GABA(A) alpha5 inverse agonist class with potential for cognitive enhancement. This class combines a modest subtype binding selectivity with inverse agonism and has the most favourable molecular properties for further lead optimisation towards a central nervous system (CNS) acting medicine.
