title: From libraries to candidate: the discovery of new ultra long-acting dibasic β₂-adrenoceptor agonists.
abstract: Libraries of dibasic compounds designed around the molecular scaffold of the DA(2)/β(2) dual agonist sibenadet (Viozan™) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious β(2)-agonist with high selectivity and a duration of action commensurable with once daily dosing.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK. dr.lilian.alcaraz@gmail.com
authors.forename: Lilian
authors.initials: L
authors.lastname: Alcaraz
authors.forename: Andrew
authors.initials: A
authors.lastname: Bailey
authors.forename: Elaine
authors.initials: E
authors.lastname: Cadogan
authors.forename: Stephen
authors.initials: S
authors.lastname: Connolly
authors.forename: Robert
authors.initials: R
authors.lastname: Jewell
authors.forename: Stephen
authors.initials: S
authors.lastname: Jordan
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kindon
authors.forename: Andrew
authors.initials: A
authors.lastname: Lister
authors.forename: Mandy
authors.initials: M
authors.lastname: Lawson
authors.forename: Alexander
authors.initials: A
authors.lastname: Mullen
authors.forename: Ian
authors.initials: I
authors.lastname: Dainty
authors.forename: David
authors.initials: D
authors.lastname: Nicholls
authors.forename: Stuart
authors.initials: S
authors.lastname: Paine
authors.forename: Garry
authors.initials: G
authors.lastname: Pairaudeau
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Stocks
authors.forename: Phillip
authors.initials: P
authors.lastname: Thorne
authors.forename: Alan
authors.initials: A
authors.lastname: Young
mesh_terms: D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D001993:Bronchodilator Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D011485:Protein Binding; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D013844:Thiazoles; D000242:Cyclic AMP; C116267:sibenadet