title: The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating a urea group.
abstract: A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a urea moiety on the terminal right-hand side phenyl ring of (R)-salmeterol is presented. Urea 9j had long duration of action in vitro on guinea pig trachea, and also in vivo similar to that of salmeterol. It had lower oral absorption and bioavailability than salmeterol in both rat and dog. It had a turnover ratio similar to salmeterol, with no evidence for formation of any aniline metabolites in human liver microsomes and hepatocytes. However no crystalline salts suitable for inhaled delivery were identified.
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: Alison J
authors.initials: AJ
authors.lastname: Ford
authors.forename: Brian E
authors.initials: BE
authors.lastname: Looker
authors.forename: Gillian E
authors.initials: GE
authors.lastname: Lunniss
authors.forename: Deborah
authors.initials: D
authors.lastname: Needham
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* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000420:Albuterol / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001247:Asthenia / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051381:Rats; D000068299:Salmeterol Xinafoate; D013237:Stereoisomerism; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D000068299:Salmeterol Xinafoate; D014508:Urea; D000420:Albuterol