title: Novel pyrrolidine melanin-concentrating hormone receptor 1 antagonists with reduced hERG inhibition.
abstract: We discovered novel pyrrolidine MCHR1 antagonist 1 possessing moderate potency. Profiling of pyrrolidine 1 demonstrated that it was an inhibitor of the hERG channel. Investigation of the structure-activity relationship of this class of pyrrolidines allowed us to optimize the MCHR1 potency and decrease the hERG inhibition. Increasing the acidity of the amide proton by converting the benzamide in lead 1 to an anilide provided single digit nanomolar MCHR1 antagonists while replacing the dimethoxyphenyl ring of 1 with alkyl groups possessing increased polarity dramatically reduced the hERG inhibition.
authors.affiliation: Department of Chemistry Research & Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Fox
authors.forename: Reina
authors.initials: R
authors.lastname: Natero
authors.forename: Kevin
authors.initials: K
authors.lastname: Richard
authors.forename: Richard
authors.initials: R
authors.lastname: Connors
authors.forename: Philip M
authors.initials: PM
authors.lastname: Roveto
authors.forename: Holger
authors.initials: H
authors.lastname: Beckmann
authors.forename: Katrin
authors.initials: K
authors.lastname: Haller
authors.forename: Justin
authors.initials: J
authors.lastname: Golde
authors.forename: Shou-Hua
authors.initials: SH
authors.lastname: Xiao
authors.forename: Frank
authors.initials: F
authors.lastname: Kayser
mesh_terms: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C103263:MCHR1 protein, human; D011759:Pyrrolidines; D017481:Receptors, Somatostatin; C032519:pyrrolidine