RESUMEN
Herein, we disclose the discovery and optimization of 2-piperidin-4-yl-acetamide derivatives as MCH-R1 antagonists. Structural investigation of piperidin-4-yl-amide and piperidin-4-yl-ureas identified 2-piperidin-4-yl-acetamide-based MCH-R1 antagonists with outstanding in vivo efficacy but flawed with high affinity towards the hERG potassium channel. While existing hERG SAR information was employed to discover highly potent MCH-R1 antagonists with minimized hERG inhibition, additional hurdles prevented their subsequent clinical exploration.
Asunto(s)
Acetamidas/síntesis química , Química Farmacéutica/métodos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Piperidinas/síntesis química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Acetamidas/farmacología , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Células CHO , Línea Celular , Cricetinae , Cricetulus , Diseño de Fármacos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/química , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Obesidad/tratamiento farmacológico , Piperidinas/farmacología , Receptores de la Hormona Hipofisaria/química , Factores de TiempoRESUMEN
The discovery and optimization of piperidin-4-yl-urea derivatives as MCH-R1 antagonists is herein described. Previous work around the piperidin-4-yl-amides led to the discovery of potent MCH-R1 antagonists. However, high affinity towards the hERG potassium channel proved to be an issue. Different strategies to increase hERG selectivity were implemented and resulted in the identification of piperidin-4-yl-urea compounds as potent MCH-R1 antagonists with minimized hERG inhibition.
Asunto(s)
Química Farmacéutica/métodos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Piperidinas/química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Urea/análogos & derivados , Urea/química , Alimentación Animal , Animales , Línea Celular , Diseño de Fármacos , Canal de Potasio ERG1 , Conducta Alimentaria , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Obesidad/tratamiento farmacológico , Unión Proteica , RatasRESUMEN
A series of 1,3-disubstituted-1H-pyrrole-based antagonists of the human Melanin-Concentrating Hormone Receptor 1 (h-MCH-R1) are reported. High-throughput screening of the AstraZeneca compound collection yielded 1, a hit with moderate affinity towards MCH-R1. Subsequent structural manipulations and SAR analysis served to rationalize potency requirements, and 12 was identified as a novel, functional MCH-R1 antagonist with favorable pharmacokinetic properties.