RESUMO
The identification and optimization of a novel series of centrally efficacious gamma secretase modulators (GSMs) offering an alternative to the privileged aryl imidazole motif is described. Chiral bicyclic tetrahydroindazolyl amine substituted triazolopyridines were identified as structurally distinct novel series of GSMs. Representative compound BI-1408 ((R)-42) was demonstrated to be centrally efficacious in rats at a 30â¯mg/kg oral dose.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Imidazóis/química , Administração Oral , Secretases da Proteína Precursora do Amiloide/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Compostos Bicíclicos com Pontes/química , Células Cultivadas , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Meia-Vida , Imidazóis/síntese química , Imidazóis/farmacocinética , Concentração Inibidora 50 , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. An evaluation of the structure-activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented.
Assuntos
Pirimidinas/química , Receptores de Glutamato Metabotrópico/química , Estirenos/química , Administração Oral , Regulação Alostérica , Animais , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Ensaios de Triagem em Larga Escala , Humanos , Modelos Animais , Atividade Motora/fisiologia , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade , Estirenos/síntese química , Estirenos/uso terapêuticoRESUMO
Stimulation of the metabotropic glutamate receptor 4 (mGluR4) represents a promising new approach to the symptomatic treatment of the neurodegenerative disorder Parkinson's disease (PD). Preclinical models using both agonists and positive allosteric modulators of mGluR4 have demonstrated the potential for this receptor for the treatment of PD. The present article evaluates a recent patent filed by Addex Pharma S.A. claiming a novel series of mGluR4 positive allosteric modulators. Many of the examples disclosed are active at EC(50)'s < 500 nM.
