title: Discovery and structure-activity relationships of 2-benzylpyrrolidine-substituted aryloxypropanols as calcium-sensing receptor antagonists.
abstract: A structure-activity relationship study of the amine portion of the calcilytic compound NPS-2143 resulted in the discovery of substituted 2-benzylpyrrolidines as replacements for the 1,1-dimethyl-2-naphthalen-2-yl-ethylamine. When compared to NPS-2143, a newly discovered compound, 3h, exhibited similar potency as a calcium-sensing receptor (CaR) antagonist and a superior human ether-a-go-go related gene (hERG) profile.
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5400, Princeton, NJ 08543-5400, USA. wu.yang@bms.com
authors.forename: Wu
authors.initials: W
authors.lastname: Yang
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Jacques Y
authors.initials: JY
authors.lastname: Roberge
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Ma
authors.forename: Yalei
authors.initials: Y
authors.lastname: Liu
authors.forename: R
authors.initials: R
authors.lastname: Michael Lawrence
authors.forename: David P
authors.initials: DP
authors.lastname: Rotella
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.forename: Jean H M
authors.initials: JH
authors.lastname: Feyen
authors.forename: John K
authors.initials: JK
authors.lastname: Dickson
mesh_terms: D020013:Calcium Signaling / Q000187:drug effects; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D020128:Inhibitory Concentration 50; D009281:Naphthalenes / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors; D020005:Propanols / Q000138:chemical synthesis* / Q000494:pharmacology; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C436740:N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine; D009281:Naphthalenes; D024642:Potassium Channels, Voltage-Gated; D020005:Propanols; D044169:Receptors, Calcium-Sensing