RESUMO
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.
Assuntos
Benzodiazepinas/química , Nootrópicos/química , Receptores de GABA-A/metabolismo , Triazóis/química , Animais , Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Descoberta de Drogas , Agonismo Inverso de Drogas , Agonistas de Receptores de GABA-A , Humanos , Nootrópicos/síntese química , Nootrópicos/farmacologia , Oócitos/efeitos dos fármacos , Triazóis/síntese química , Triazóis/farmacologia , Xenopus laevisRESUMO
A novel class of 4-substituted-8-(1-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu opioid receptor as well as the nociceptin/orphanin FQ peptide (NOP) receptor. These molecules also exhibit superior pharmacological and pharmacokinetic parameters, relative to all GlyT1 inhibitors of the spiropiperidine family, culminating in the identification of 16b with an oral bioavailability of approximately 60%. In addition, a straightforward two-step procedure for the assembly of the target molecules is also presented.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina/química , Piperidinas/farmacologia , Compostos de Espiro/farmacologia , Administração Oral , Animais , Canais de Potássio Éter-A-Go-Go/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Cinética , Camundongos , Microssomos , Modelos Químicos , Peptídeos Opioides/química , Piperidinas/química , Ligação Proteica , Isoformas de Proteínas , Compostos de Espiro/química , Temperatura , NociceptinaRESUMO
A novel class of 4-aryl-8-(2-hydroxy-2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1- ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu-opioid receptor as well as the Nociceptin/Orphanin FQ peptide (NOP) receptor. In particular these novel compounds 4 as well as the 4-substituted-8-(2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one 3 show improved metabolic stability and pharmacokinetic profiles in rodents compared to previous triazaspiropiperidine series 1 and 2. We have also identified within these diazaspiropiperidine series a key relationship between reducing basicity of the piperidine nitrogen and reducing hERG affinity.
Assuntos
Canais de Potássio Éter-A-Go-Go/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Peptídeos Opioides/química , Animais , Química Farmacêutica , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Camundongos , Microssomos/metabolismo , Modelos Químicos , Peptídeos/química , Isoformas de Proteínas , Receptores Opioides/química , NociceptinaRESUMO
A novel class of 4-substituted-8-(2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu opioid receptor as well as the nociceptin/orphanin FQ peptide (NOP) receptor. A novel, straightforward and efficient synthetic strategy for the assembly of the target molecules is also presented.