RESUMO
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.
Assuntos
Acetamidas/síntese química , Química Farmacêutica/métodos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Piperidinas/síntese química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Acetamidas/farmacologia , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Desenho de Fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/química , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Obesidade/tratamento farmacológico , Piperidinas/farmacologia , Receptores do Hormônio Hipofisário/química , Fatores de TempoRESUMO
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.
Assuntos
Química Farmacêutica/métodos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Piperidinas/química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/química , Ração Animal , Animais , Linhagem Celular , Desenho de Fármacos , Canal de Potássio ERG1 , Comportamento Alimentar , Humanos , Concentração Inibidora 50 , Modelos Químicos , Obesidade/tratamento farmacológico , Ligação Proteica , RatosRESUMO
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.