title: QSAR and the rational design of long-acting dual D2-receptor/beta 2-adrenoceptor agonists.
abstract: This paper describes the development of a QSAR model for the rational control of functional duration of topical long-acting dual D(2)-receptor/beta(2)-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease. A QSAR model highlighted the importance of lipophilicity and ionization in controlling beta(2) duration. It was found that design rules logD(7.4) > 2, secondary amine pK(a) > 8.0, yielded ultra-long duration compounds. This model was used successfully to guide the design of long- and ultra-long-acting compounds. The QSAR model is discussed in terms of the exosite model, and the plasmalemma diffusion microkinetic hypothesis, for the control of beta(2) duration. Data presented strongly suggests that beta(2) duration is primarily controlled by the membrane affinity of these compounds.
authors.affiliation: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
authors.forename: Rupert P
authors.initials: RP
authors.lastname: Austin
authors.forename: Patrick
authors.initials: P
authors.lastname: Barton
authors.forename: Roger V
authors.initials: RV
authors.lastname: Bonnert
authors.forename: Roger C
authors.initials: RC
authors.lastname: Brown
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cage
authors.forename: David R
authors.initials: DR
authors.lastname: Cheshire
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davis
authors.forename: Iain G
authors.initials: IG
authors.lastname: Dougall
authors.forename: Francis
authors.initials: F
authors.lastname: Ince
authors.forename: Garry
authors.initials: G
authors.lastname: Pairaudeau
authors.forename: Alan
authors.initials: A
authors.lastname: Young
mesh_terms: D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000420:Albuterol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000465:Algorithms; D000818:Animals; D001692:Biological Transport; D018491:Dopamine Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D008958:Models, Molecular; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D021281:Quantitative Structure-Activity Relationship; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects*; D000068299:Salmeterol Xinafoate; D014132:Trachea / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D018491:Dopamine Agonists; D018343:Receptors, Adrenergic, beta-2; D000068299:Salmeterol Xinafoate; D000420:Albuterol