RESUMEN
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.
Asunto(s)
Benzodiazepinas/química , Nootrópicos/química , Receptores de GABA-A/metabolismo , Triazoles/química , Animales , Benzodiazepinas/síntesis química , Benzodiazepinas/farmacología , Descubrimiento de Drogas , Agonismo Inverso de Drogas , Agonistas de Receptores de GABA-A , Humanos , Nootrópicos/síntesis química , Nootrópicos/farmacología , Oocitos/efectos de los fármacos , Triazoles/síntesis química , Triazoles/farmacología , Xenopus laevisRESUMEN
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.
Asunto(s)
Proteínas de Transporte de Glicina en la Membrana Plasmática/química , Piperidinas/farmacología , Compuestos de Espiro/farmacología , Administración Oral , Animales , Canales de Potasio Éter-A-Go-Go/metabolismo , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Humanos , Concentración 50 Inhibidora , Cinética , Ratones , Microsomas , Modelos Químicos , Péptidos Opioides/química , Piperidinas/química , Unión Proteica , Isoformas de Proteínas , Compuestos de Espiro/química , Temperatura , NociceptinaRESUMEN
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.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/metabolismo , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Péptidos Opioides/química , Animales , Química Farmacéutica , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Cinética , Ratones , Microsomas/metabolismo , Modelos Químicos , Péptidos/química , Isoformas de Proteínas , Receptores Opioides/química , NociceptinaRESUMEN
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.