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
The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Benzazepinas/síntesis química , Obesidad/tratamiento farmacológico , Agonistas del Receptor de Serotonina 5-HT2 , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/farmacología , Benzazepinas/farmacocinética , Benzazepinas/farmacología , Línea Celular , Ingestión de Alimentos/efectos de los fármacos , Humanos , Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Aumento de Peso/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
We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT(2C) receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT(2C), h5-HT(2A) or h5-HT(2B) receptors. Several compounds are shown to be potent and selective 5-HT(2C) receptor agonists, which decrease food intake in a rat feeding model.