RESUMO
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.