RESUMO
We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this article, we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine-substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. The fine tuning of metabolism and hERG followed by differentiation of advanced leads that were identified on the basis of PK profiles and in vivo potency converged on lead compound 36 (JNJ-40411813). Full in vitro and in vivo profiles indicate that 36 displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Compound 36 has been investigated in the clinic for schizophrenia and anxious depression disorders.
Assuntos
Ansiolíticos/química , Antipsicóticos/química , Piperidinas/química , Piridonas/química , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica , Animais , Ansiolíticos/síntese química , Ansiolíticos/farmacologia , Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Células CHO , Cricetulus , Cães , Canal de Potássio ERG1 , Eletroencefalografia , Canais de Potássio Éter-A-Go-Go/fisiologia , Células HEK293 , Humanos , Masculino , Técnicas de Patch-Clamp , Piperidinas/síntese química , Piperidinas/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Ensaio Radioligante , Ratos Sprague-Dawley , Sono/efeitos dos fármacos , Relação Estrutura-Atividade , Vigília/efeitos dos fármacosRESUMO
The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep-wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.
Assuntos
Nitrilas/síntese química , Piridonas/síntese química , Receptores de Glutamato Metabotrópico/agonistas , Regulação Alostérica , Animais , Encéfalo/metabolismo , Sinergismo Farmacológico , Canal de Potássio ERG1 , Eletroencefalografia , Canais de Potássio Éter-A-Go-Go/fisiologia , Células HEK293 , Humanos , Isomerismo , Camundongos , Nitrilas/farmacocinética , Nitrilas/farmacologia , Técnicas de Patch-Clamp , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Sono REM/efeitos dos fármacos , Relação Estrutura-Atividade , VigíliaRESUMO
Advanced leads of an imidazopyridine series of positive allosteric modulators of the metabotropic glutamate 2 (mGlu2) receptor are reported. The optimization of in vitro ADMET and in vivo pharmacokinetic properties led to the identification of 27o. With good potency and selectivity for the mGlu2 receptor, 27o affected sleep-wake architecture in rats after oral treatment, which we have previously shown to be indicative of mGlu2 receptor-mediated central activity.
