title: 4-Piperidin-4-ylidenemethyl-benzamides as δ-opioid receptor agonists for CNS indications: identifying clinical candidates.
abstract: A series of 4-piperidin-4-ylidenemethyl-benzamide δ-opioid receptor agonists is described with an emphasis on balancing the potency, subtype selectivity and in vitro ADME and safety properties. The three sites impacting SAR are substitutions on the aryl group (R(1)), the piperidine nitrogen (R(2)), and the amide (R(3)). Each region contributes to the balance of properties for δ opioid activity and a desirable CNS profile, and two clinical candidates (20 and 24) were advanced.
authors.affiliation: AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA.
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: John P
authors.initials: JP
authors.lastname: McCauley
authors.forename: Donald W
authors.initials: DW
authors.lastname: Andisik
authors.forename: Kelly
authors.initials: K
authors.lastname: Brush
authors.forename: Khanh H
authors.initials: KH
authors.lastname: Bui
authors.forename: William
authors.initials: W
authors.lastname: Frietze
authors.forename: Valerie
authors.initials: V
authors.lastname: Hoesch
authors.forename: Jay
authors.initials: J
authors.lastname: Liu
authors.forename: William E
authors.initials: WE
authors.lastname: Palmer
authors.forename: Nathan
authors.initials: N
authors.lastname: Spear
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudzik
authors.forename: Steven S
authors.initials: SS
authors.lastname: Wesolowski
mesh_terms: D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D051638:Ether-A-Go-Go Potassium Channels; D010880:Piperidines; D017465:Receptors, Opioid, delta