title: Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach.
abstract: A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. pan.a.procopiou@gsk.com
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Procopiou
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Barrett
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Bevan
authors.forename: Keith
authors.initials: K
authors.lastname: Biggadike
authors.forename: Philip C
authors.initials: PC
authors.lastname: Box
authors.forename: Peter R
authors.initials: PR
authors.lastname: Butchers
authors.forename: Diane M
authors.initials: DM
authors.lastname: Coe
authors.forename: Richard
authors.initials: R
authors.lastname: Conroy
authors.forename: Amanda
authors.initials: A
authors.lastname: Emmons
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Ford
authors.forename: Duncan S
authors.initials: DS
authors.lastname: Holmes
authors.forename: Helen
authors.initials: H
authors.lastname: Horsley
authors.forename: Fern
authors.initials: F
authors.lastname: Kerr
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Li-Kwai-Cheung
authors.forename: Brian E
authors.initials: BE
authors.lastname: Looker
authors.forename: Inderjit S
authors.initials: IS
authors.lastname: Mann
authors.forename: Iain M
authors.initials: IM
authors.lastname: McLay
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Morrison
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mutch
authors.forename: Claire E
authors.initials: CE
authors.lastname: Smith
authors.forename: Paula
authors.initials: P
authors.lastname: Tomlin
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D019905:Benzyl Alcohol / Q000737:chemistry; D001592:Benzyl Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D002722:Chlorobenzenes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D001592:Benzyl Alcohols; D002722:Chlorobenzenes; D018343:Receptors, Adrenergic, beta-2; C550468:vilanterol; D019905:Benzyl Alcohol