ABSTRACT
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.
Subject(s)
Acetamides/chemical synthesis , Chemistry, Pharmaceutical/methods , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Piperidines/chemical synthesis , Receptors, Pituitary Hormone/antagonists & inhibitors , Acetamides/pharmacology , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , CHO Cells , Cell Line , Cricetinae , Cricetulus , Drug Design , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/chemistry , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Obesity/drug therapy , Piperidines/pharmacology , Receptors, Pituitary Hormone/chemistry , Time FactorsABSTRACT
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.
Subject(s)
Chemistry, Pharmaceutical/methods , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Piperidines/chemistry , Receptors, Pituitary Hormone/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemistry , Animal Feed , Animals , Cell Line , Drug Design , ERG1 Potassium Channel , Feeding Behavior , Humans , Inhibitory Concentration 50 , Models, Chemical , Obesity/drug therapy , Protein Binding , RatsABSTRACT
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.