title: Optimization of piperidin-4-yl-urea-containing melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Reducing hERG-associated liabilities.
abstract: 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.
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D Mölndal, Pepparedsleden 1, SE-431 83, Mölndal, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Berglund
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Egner
authors.forename: Henrik
authors.initials: H
authors.lastname: Gradén
authors.forename: Joakim
authors.initials: J
authors.lastname: Gradén
authors.forename: David G A
authors.initials: DG
authors.lastname: Morgan
authors.forename: Tord
authors.initials: T
authors.lastname: Inghardt
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
mesh_terms: 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*
chemical_list: 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