Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach.
Publication/Presentation Date
6-10-2010
Abstract
A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.
Volume
53
Issue
11
First Page
4522
Last Page
4530
ISSN
1520-4804
Published In/Presented At
Procopiou, P. A., Barrett, V. J., Bevan, N. J., Biggadike, K., Box, P. C., Butchers, P. R., Coe, D. M., Conroy, R., Emmons, A., Ford, A. J., Holmes, D. S., Horsley, H., Kerr, F., Li-Kwai-Cheung, A. M., Looker, B. E., Mann, I. S., McLay, I. M., Morrison, V. S., Mutch, P. J., Smith, C. E., … Tomlin, P. (2010). Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach. Journal of medicinal chemistry, 53(11), 4522–4530. https://doi.org/10.1021/jm100326d
Disciplines
Medicine and Health Sciences
PubMedID
20462258
Department(s)
Department of Medicine
Document Type
Article