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.
MeSH terms
-
Acetamides / chemical synthesis*
-
Acetamides / pharmacology
-
Animals
-
Anti-Obesity Agents / chemical synthesis
-
Anti-Obesity Agents / pharmacology
-
CHO Cells
-
Cell Line
-
Chemistry, Pharmaceutical / methods*
-
Cricetinae
-
Cricetulus
-
Drug Design
-
ERG1 Potassium Channel
-
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
-
Ether-A-Go-Go Potassium Channels / chemistry
-
Humans
-
Inhibitory Concentration 50
-
Mice
-
Models, Chemical
-
Obesity / drug therapy
-
Piperidines / chemical synthesis*
-
Piperidines / pharmacology
-
Receptors, Pituitary Hormone / antagonists & inhibitors*
-
Receptors, Pituitary Hormone / chemistry
-
Time Factors
Substances
-
Acetamides
-
Anti-Obesity Agents
-
ERG1 Potassium Channel
-
Ether-A-Go-Go Potassium Channels
-
KCNH2 protein, human
-
Piperidines
-
Receptors, Pituitary Hormone
-
melanin-concentrating hormone receptor