Optimization of piperidin-4-yl-urea-containing melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Reducing hERG-associated liabilities.
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.
Berglund
Susanne
S
Medicinal Chemistry, AstraZeneca R&D Mölndal, Pepparedsleden 1, SE-431 83, Mölndal, Sweden.
Egner
Bryan J
BJ
Gradén
Henrik
H
Gradén
Joakim
J
Morgan
David G A
DG
Inghardt
Tord
T
Giordanetto
Fabrizio
F
D000821:Animal Feed; D000818:Animals; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D005247:Feeding Behavior; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D009765:Obesity / Q000188:drug therapy; D010880:Piperidines / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry*
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010880:Piperidines; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor; D014508:Urea