RESUMEN
The synthesis and SAR of a series of 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine P2X7 antagonists are described. Addressing P2X7 affinity and liver microsomal stability issues encountered with this template afforded methyl substituted 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridines ultimately leading to the identification of 1 (JNJ 54166060). 1 is a potent P2X7 antagonist with an ED50 = 2.3 mg/kg in rats, high oral bioavailability and low-moderate clearance in preclinical species, acceptable safety margins in rats, and a predicted human dose of 120 mg of QD. Additionally, 1 possesses a unique CYP profile and was found to be a regioselective inhibitor of midazolam CYP3A metabolism.
Asunto(s)
Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/farmacología , Piridinas/química , Piridinas/farmacología , Receptores Purinérgicos P2X7/metabolismo , Administración Oral , Animales , Perros , Halogenación , Haplorrinos , Humanos , Imidazoles/administración & dosificación , Imidazoles/química , Imidazoles/farmacocinética , Imidazoles/farmacología , Ratones , Modelos Moleculares , Antagonistas del Receptor Purinérgico P2X/administración & dosificación , Antagonistas del Receptor Purinérgico P2X/farmacocinética , Piridinas/administración & dosificación , Piridinas/farmacocinética , RatasRESUMEN
Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacología , Indoles/síntesis química , Indoles/farmacología , Tiofenos/síntesis química , Tiofenos/farmacología , Animales , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Indicadores y Reactivos , Indoles/farmacocinética , Isomerismo , Modelos Moleculares , Ratas , Relación Estructura-Actividad , Tiofenos/farmacocinéticaRESUMEN
The pre-clinical characterization of novel aryloxypyridine amides that are histamine H(3) receptor antagonists is described. These compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates.
Asunto(s)
Azepinas/farmacología , Antagonistas de los Receptores Histamínicos H3/farmacología , Piridinas/farmacología , Amidas/química , Animales , Azepinas/química , Evaluación Preclínica de Medicamentos , Piridinas/química , RatasRESUMEN
Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H(3) receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H(3) receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate.
