RESUMO
Scaffold hopping from a non-basic series of 5-HT(2A) receptor antagonists developed in-house that possessed reduced activity in vivo enabled the discovery of a novel series of diaryl sulfones that gave excellent occupancy on oral dosing. Not only does this work further demonstrate that oral bioavailability of a given series can be enhanced by improving physicochemical parameters such as log P, but it corroborates the growing evidence that a protonated amine is not essential for affinity at aminergic GPCRs.
Assuntos
Antagonistas do Receptor 5-HT2 de Serotonina , Sulfonas/síntese química , Administração Oral , Aminas , Animais , Disponibilidade Biológica , Descoberta de Drogas , Humanos , Ligantes , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Agonistas do Receptor de Serotonina , Transtornos do Sono-Vigília/tratamento farmacológico , Sulfonas/farmacologia , Sulfonas/uso terapêuticoRESUMO
8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochemical mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochemical mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 3 acts as a bioisosteric replacement for imidazopyrimidine in the GABA(A) receptor modulator 2.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Agonistas GABAérgicos/síntese química , Agonistas de Receptores de GABA-A , Imidazóis/síntese química , Piridinas/síntese química , Animais , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Agonistas GABAérgicos/química , Agonistas GABAérgicos/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Ligantes , Camundongos , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Proteínas Recombinantes/agonistas , Relação Estrutura-AtividadeRESUMO
Incorporation of fluorine at the 4-position of an existing series of sulfonyl piperidine 5-HT2A antagonists gave compounds with increased selectivity over the IKr potassium channel. This work led to the identification of 3b, a compound that gave no increase in QTc in the anesthetized dog up to plasma levels as high as 148 microM. Furthermore, 3b has been shown to increase slow-wave sleep bout duration and to decrease the number of awakenings in rats, indicating the potential utility of 5-HT2A antagonists in the treatment of insomnia.
Assuntos
Piperidinas/farmacologia , Piperidinas/uso terapêutico , Antagonistas do Receptor 5-HT2 de Serotonina , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Ligantes , Estrutura Molecular , Piperidinas/síntese química , Ratos , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Nonselective inverse agonists at the gamma-aminobutyric acid(A) (GABA-A) benzodiazepine binding site have cognition-enhancing effects in animals but are anxiogenic and can precipitate convulsions. Herein, we describe novel GABA-A alpha5 subtype inverse agonists leading to the identification of 16 as an orally active, functionally selective compound that enhances cognition in animals without anxiogenic or convulsant effects. Compounds of this type may be useful in the symptomatic treatment of memory impairment associated with Alzheimer's disease and related dementias.