title: The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating hydantoin or uracil rings.
abstract: A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of (R)-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12h in guinea pigs in vivo at its EC(90) 25 μM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m.
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: Peter R
authors.initials: PR
authors.lastname: Butchers
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: Séverine
authors.initials: S
authors.lastname: Jeulin
authors.forename: Brian E
authors.initials: BE
authors.lastname: Looker
authors.forename: Gillian E
authors.initials: GE
authors.lastname: Lunniss
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Morrison
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mutch
authors.forename: Rossana
authors.initials: R
authors.lastname: Perciaccante
authors.forename: Mark
authors.initials: M
authors.lastname: Ruston
authors.forename: Claire E
authors.initials: CE
authors.lastname: Smith
authors.forename: Graham
authors.initials: G
authors.lastname: Somers
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; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D006168:Guinea Pigs; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006827:Hydantoins / Q000737:chemistry*; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D013237:Stereoisomerism; D014132:Trachea / Q000187:drug effects; D014498:Uracil / Q000737:chemistry*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D006827:Hydantoins; D018343:Receptors, Adrenergic, beta-2; D014498:Uracil