title: Optimization of 2-piperidin-4-yl-acetamides as melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Designing out hERG inhibition.
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.
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: D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000494:pharmacology; D016466:CHO Cells; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D009765:Obesity / Q000188:drug therapy; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013997:Time Factors
chemical_list: D000081:Acetamides; D019440:Anti-Obesity Agents; 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