title: Multiparameter exploration of piperazine derivatives as δ-opioid receptor agonists for CNS indications.
abstract: A novel series of piperazine derivatives exhibits sub-nanomolar binding and enhanced subtype selectivity as δ-opioid agonists. The synthesis and SAR are described as well as the application of computational models to improve in vitro ADME and safety properties suitable for CNS indications, specifically microsomal clearance, permeability, and hERG channel inhibition.
authors.affiliation: AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: McCauley
authors.forename: Cathy L
authors.initials: CL
authors.lastname: Dantzman
authors.forename: Megan M
authors.initials: MM
authors.lastname: King
authors.forename: Glen E
authors.initials: GE
authors.lastname: Ernst
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Kelly
authors.initials: K
authors.lastname: Brush
authors.forename: William E
authors.initials: WE
authors.lastname: Palmer
authors.forename: William
authors.initials: W
authors.lastname: Frietze
authors.forename: Donald W
authors.initials: DW
authors.lastname: Andisik
authors.forename: Valerie
authors.initials: V
authors.lastname: Hoesch
authors.forename: Kenneth
authors.initials: K
authors.lastname: Doring
authors.forename: James
authors.initials: J
authors.lastname: Hulsizer
authors.forename: Khanh H
authors.initials: KH
authors.lastname: Bui
authors.forename: Jay
authors.initials: J
authors.lastname: Liu
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudzik
authors.forename: Steven S
authors.initials: SS
authors.lastname: Wesolowski
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D003198:Computer Simulation; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D010879:Piperazines; D017465:Receptors, Opioid, delta