RESUMO
The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.
Assuntos
Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Antagonistas dos Receptores Histamínicos/química , Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores Histamínicos H3/química , Sulfonas/química , Animais , Área Sob a Curva , Encéfalo/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Química Farmacêutica/métodos , Desenho de Fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/química , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Pirrolidinas/antagonistas & inibidores , Ratos , Sono/efeitos dos fármacos , Temperatura , Vigília/efeitos dos fármacosRESUMO
Antagonism of the histamine-H(3) receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as excessive daytime sleepiness (EDS) as well as other sleep or cognitive disorders. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were shown to be potent and selective antagonists of the H(3) receptor. Several of these compounds demonstrated in vivo activity in a rat model of (R)-alpha-methyl histamine (RAMH) induced dipsogenia, and one compound (4e) provided an increase in wakefulness in rats as measured by polysomnographic methods. However, more detailed analysis of the PK/PD relationship suggested the presence of a common active metabolite which may preclude this series of compounds from further development.
Assuntos
Compostos de Bifenilo/química , Desenho de Fármacos , Agonismo Inverso de Drogas , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H3/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Administração Oral , Animais , Antagonistas dos Receptores Histamínicos/administração & dosagem , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sede/efeitos dos fármacos , Vigília/efeitos dos fármacosRESUMO
A new series of H(3) antagonists derived from the natural product Conessine are presented. Several compounds from these new series retain the potency and selectivity of earlier diamine based analogs while exhibiting improved PK characteristics. One compound (3u) demonstrated functional antagonism of the H(3) receptor in an in vivo pharmacological model.
Assuntos
Alcaloides/farmacocinética , Química Farmacêutica/métodos , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H3/química , Animais , Ligação Competitiva/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Desenho de Fármacos , Antagonistas dos Receptores Histamínicos/química , Cinética , Modelos Químicos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
A new family of Histamine H(3) receptor antagonists (5a-t) has been prepared based on the structure of the natural product Conessine, a known H(3) antagonist. Several members of the new series are highly potent and selective binders of rat and human H(3) receptors and display inverse agonism at the human H(3) receptor. Compound 5n exhibited promising rat pharmacokinetic properties and demonstrated functional antagonism of the H(3) receptor in an in-vivo pharmacological model.
