QSAR and the rational design of long-acting dual D2-receptor/beta 2-adrenoceptor agonists.
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.
Austin
Rupert P
RP
AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
Barton
Patrick
P
Bonnert
Roger V
RV
Brown
Roger C
RC
Cage
Peter A
PA
Cheshire
David R
DR
Davis
Andrew M
AM
Dougall
Iain G
IG
Ince
Francis
F
Pairaudeau
Garry
G
Young
Alan
A
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
D000318:Adrenergic beta-Agonists; D018491:Dopamine Agonists; D018343:Receptors, Adrenergic, beta-2; D000068299:Salmeterol Xinafoate; D000420:Albuterol