title: The discovery of CCR3/H1 dual antagonists with reduced hERG risk.
abstract: A series of dual CCR3/H(1) antagonists based on a bispiperidine scaffold were discovered. Introduction of an acidic group overcame hERG liability. Bioavailability was optimised by modulation of physico-chemical properties and physical form to deliver a compound suitable for clinical evaluation.
authors.affiliation: Department of Bioscience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, United Kingdom.
authors.forename: Ash
authors.initials: A
authors.lastname: Bahl
authors.forename: Patrick
authors.initials: P
authors.lastname: Barton
authors.forename: Keith
authors.initials: K
authors.lastname: Bowers
authors.forename: Steven
authors.initials: S
authors.lastname: Brough
authors.forename: Richard
authors.initials: R
authors.lastname: Evans
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Luckhurst
authors.forename: Tobias
authors.initials: T
authors.lastname: Mochel
authors.forename: Matthew W D
authors.initials: MW
authors.lastname: Perry
authors.forename: Aaron
authors.initials: A
authors.lastname: Rigby
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Riley
authors.forename: Hitesh
authors.initials: H
authors.lastname: Sanganee
authors.forename: Adam
authors.initials: A
authors.lastname: Sisson
authors.forename: Brian
authors.initials: B
authors.lastname: Springthorpe
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004347:Drug Interactions; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006634:Histamine H1 Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry; D051381:Rats; D054397:Receptors, CCR3 / Q000037:antagonists & inhibitors*; D012307:Risk Factors
chemical_list: C515350:CCR3 protein, human; D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; C496884:KCNH1 protein, human; D010880:Piperidines; D054397:Receptors, CCR3; C032727:piperidine