RESUMEN
An initial SAR study resulted in the identification of the novel, potent MCHR1 antagonist 2. After further profiling, compound 2 was discovered to be a potent inhibitor of the hERG potassium channel, which prevented its further development. Additional optimization of this structure resulted in the discovery of the potent MCHR1 antagonist 11 with a dramatically reduced hERG liability. The decrease in hERG activity was confirmed by several in vivo preclinical cardiovascular studies examining QT prolongation. This compound demonstrated good selectivity for MCHR1 and possessed good pharmacokinetic properties across preclinical species. Compound 11 was also efficacious in reducing body weight in two in vivo mouse models. This compound was selected for clinical evaluation and was given the code AMG 076.
Asunto(s)
Carbazoles/química , Ácidos Ciclohexanocarboxílicos/química , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Animales , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Carbazoles/síntesis química , Carbazoles/farmacocinética , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácidos Ciclohexanocarboxílicos/farmacocinética , Dieta Alta en Grasa , Perros , Evaluación Preclínica de Medicamentos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratas , Receptores de la Hormona Hipofisaria/genética , Receptores de la Hormona Hipofisaria/metabolismo , Relación Estructura-ActividadRESUMEN
Several beta-amino tetrazole analogs of gabapentin 1 and pregabalin 2 were prepared by one of two convergent, highly efficient routes, and their affinity for the alpha(2)-delta protein examined. Two select compounds with potent affinity for alpha(2)-delta, 8a and 16a, were subsequently tested in vivo in an audiogenic seizure model and found to elicit protective effects.
Asunto(s)
Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Ácidos Carboxílicos/química , Epilepsia Refleja/prevención & control , Ácido gamma-Aminobutírico/análogos & derivados , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Animales , Anticonvulsivantes/química , Sitios de Unión , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Gabapentina , Ratones , Ratones Endogámicos DBA , Estructura Molecular , Pregabalina , Subunidades de Proteína/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Ácido gamma-Aminobutírico/síntesis química , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
A series of carboxylate bioisosteres of structures related to gabapentin 1 have been prepared. When the carboxylate was replaced by a tetrazole, this group was recognized by the alpha2-delta protein. Further characterization of alpha2-delta binding compounds 14a and 14b revealed a similar pattern of functional in vitro and in vivo activity to gabapentin 1.