RESUMEN
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.
Asunto(s)
Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Antagonistas de los Receptores Histamínicos/química , Pirrolidinas/química , Pirrolidinas/farmacología , Receptores Histamínicos H3/química , Sulfonas/química , Animales , Área Bajo la Curva , Encéfalo/metabolismo , Sistema Nervioso Central/efectos de los fármacos , Química Farmacéutica/métodos , Diseño de Fármacos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/química , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Pirrolidinas/antagonistas & inhibidores , Ratas , Sueño/efectos de los fármacos , Temperatura , Vigilia/efectos de los fármacosRESUMEN
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.
Asunto(s)
Compuestos de Bifenilo/química , Diseño de Fármacos , Agonismo Inverso de Drogas , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacología , Administración Oral , Animales , Antagonistas de los Receptores Histamínicos/administración & dosificación , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sed/efectos de los fármacos , Vigilia/efectos de los fármacosRESUMEN
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.