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.