Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach.
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.
Procopiou
Panayiotis A
PA
Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. pan.a.procopiou@gsk.com
Barrett
Victoria J
VJ
Bevan
Nicola J
NJ
Biggadike
Keith
K
Box
Philip C
PC
Butchers
Peter R
PR
Coe
Diane M
DM
Conroy
Richard
R
Emmons
Amanda
A
Ford
Alison J
AJ
Holmes
Duncan S
DS
Horsley
Helen
H
Kerr
Fern
F
Li-Kwai-Cheung
Anne-Marie
AM
Looker
Brian E
BE
Mann
Inderjit S
IS
McLay
Iain M
IM
Morrison
Valerie S
VS
Mutch
Peter J
PJ
Smith
Claire E
CE
Tomlin
Paula
P
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D019905:Benzyl Alcohol / Q000737:chemistry; D001592:Benzyl Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D002722:Chlorobenzenes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D013329:Structure-Activity Relationship
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D001592:Benzyl Alcohols; D002722:Chlorobenzenes; D018343:Receptors, Adrenergic, beta-2; C550468:vilanterol; D019905:Benzyl Alcohol