title: Discovery of a rapidly metabolized, long-acting β(2) adrenergic receptor agonist with a short onset time incorporating a sulfone group suitable for once-daily dosing.
abstract: A series of novel, potent, and selective human β2 adrenoceptor agonists incorporating a sulfone moiety on the terminal right-hand-side phenyl ring of (R)-salmeterol is presented. Sulfone 10b had salmeterol-like potency and selectivity profile, long duration of action on guinea pig trachea, and longer than salmeterol duration of action in vivo, suitable for once-daily dosing. It had lower than salmeterol oral absorption in rat, lower bioavailability in rat and dog, and a high turnover in human hepatocytes. It was metabolized in human hepatocytes by hydroxylation, oxidation, cleavage, and conjugation; most of the metabolites would be expected to have reduced or no β2 activity. The 4-biphenylsulfonic acid was identified as a crystalline, non-hygroscopic salt of 10b, suitable for inhaled delivery. Furthermore, it was free of any genetic toxicity issues and was considered as a backup to vilanterol.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Procopiou
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Barrett
authors.forename: Keith
authors.initials: K
authors.lastname: Biggadike
authors.forename: Peter R
authors.initials: PR
authors.lastname: Butchers
authors.forename: Andrew
authors.initials: A
authors.lastname: Craven
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Ford
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Guntrip
authors.forename: Duncan S
authors.initials: DS
authors.lastname: Holmes
authors.forename: Sara C
authors.initials: SC
authors.lastname: Hughes
authors.forename: Anne E
authors.initials: AE
authors.lastname: Jones
authors.forename: Brian E
authors.initials: BE
authors.lastname: Looker
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mutch
authors.forename: Mark
authors.initials: M
authors.lastname: Ruston
authors.forename: Deborah
authors.initials: D
authors.lastname: Needham
authors.forename: Claire E
authors.initials: CE
authors.lastname: Smith
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004334:Drug Administration Schedule; D055808:Drug Discovery; D006168:Guinea Pigs; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051381:Rats; D013450:Sulfones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D013450:Sulfones