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
Metabotropic glutamate receptor 7 (mGlu(7)) has been suggested to be a promising novel target for treatment of a range of disorders, including anxiety, post-traumatic stress disorder, depression, drug abuse, and schizophrenia. Here we characterized a potent and selective mGlu(7) negative allosteric modulator (NAM) (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one (ADX71743). In vitro, Schild plot analysis and reversibility tests at the target confirmed the NAM properties of the compound and attenuation of L-(+)-2-amino-4-phosphonobutyric acid-induced synaptic depression confirmed activity at the native receptor. The pharmacokinetic analysis of ADX71743 in mice and rats revealed that it is bioavailable after s.c. administration and is brain penetrant (cerebrospinal fluid concentration/total plasma concentration ratio at C(max) = 5.3%). In vivo, ADX71743 (50, 100, 150 mg/kg, s.c.) caused no impairment of locomotor activity in rats and mice or activity on rotarod in mice. ADX71743 had an anxiolytic-like profile in the marble burying and elevated plus maze tests, dose-dependently reducing the number of buried marbles and increasing open arm exploration, respectively. Whereas ADX71743 caused a small reduction in amphetamine-induced hyperactivity in mice, it was inactive in the mouse 2,5-dimethoxy-4-iodoamphetamine-induced head twitch and the rat conditioned avoidance response tests. In addition, the compound was inactive in the mouse forced swim test. These data suggest that ADX71743 is a suitable compound to help unravel the physiologic role of mGlu(7) and to better understand its implication in central nervous system diseases. Our in vivo tests using ADX71743, reported here, suggest that pharmacological inhibition of mGlu(7) is a valid approach for developing novel pharmacotherapies to treat anxiety disorders, but may not be suitable for treatment of depression or psychosis.
Assuntos
Comportamento Animal/efeitos dos fármacos , Oxazolona/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica , Anfetamina/farmacologia , Animais , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/metabolismo , Linhagem Celular , Pareamento Cromossômico/efeitos dos fármacos , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Feminino , Células HEK293 , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Oxazolona/farmacocinética , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologiaRESUMO
A series of N-propyl-8-chloro-6-substituted isoquinolones was identified as positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2 PAM) via high throughput screening (HTS). The subsequent synthesis and initial SAR exploration that led to the identification of compound 28 is described.
Assuntos
Piridinas/síntese química , Quinolonas/química , Receptores de Glutamato Metabotrópico/química , Regulação Alostérica , Ensaios de Triagem em Larga Escala , Humanos , Microssomos Hepáticos/metabolismo , Piridinas/química , Piridinas/farmacologia , Quinolonas/síntese química , Quinolonas/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.