title: Discovery and evolution of phenoxypiperidine hydroxyamide dual CCR3/H₁ antagonists. Part II: optimising in vivo clearance.
abstract: The second part of this communication focuses on the resolution of issues surrounding the series of hydroxyamide phenoxypiperidine CCR3/H(1) dual antagonists described in Part I. This involved further structural exploration directed at reducing metabolism and leading to the identification of compound 60 with a greatly improved in vivo pharmacokinetic profile.
authors.affiliation: AstraZeneca Respiratory & Inflammation iMED, Pepparedsleden 1, 431 83 Mölndal, Sweden. mark1.furber@astrazeneca.com
authors.forename: Mark
authors.initials: M
authors.lastname: Furber
authors.forename: Lilian
authors.initials: L
authors.lastname: Alcaraz
authors.forename: Christopher
authors.initials: C
authors.lastname: Luckhurst
authors.forename: Ash
authors.initials: A
authors.lastname: Bahl
authors.forename: Haydn
authors.initials: H
authors.lastname: Beaton
authors.forename: Keith
authors.initials: K
authors.lastname: Bowers
authors.forename: John
authors.initials: J
authors.lastname: Collington
authors.forename: Rebecca
authors.initials: R
authors.lastname: Denton
authors.forename: David
authors.initials: D
authors.lastname: Donald
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kinchin
authors.forename: Cathy
authors.initials: C
authors.lastname: MacDonald
authors.forename: Aaron
authors.initials: A
authors.lastname: Rigby
authors.forename: Rob
authors.initials: R
authors.lastname: Riley
authors.forename: Matt
authors.initials: M
authors.lastname: Soars
authors.forename: Brian
authors.initials: B
authors.lastname: Springthorpe
authors.forename: Peter
authors.initials: P
authors.lastname: Webborn
mesh_terms: D000818:Animals; D004285:Dogs; D055808:Drug Discovery; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D054397:Receptors, CCR3 / Q000037:antagonists & inhibitors*; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C515350:CCR3 protein, human; D010880:Piperidines; D054397:Receptors, CCR3; D011969:Receptors, Histamine H1