686350-93-6Relevant articles and documents
Discovery of a rapidly metabolized, long-acting β2 adrenergic receptor agonist with a short onset time incorporating a sulfone group suitable for once-daily dosing
Procopiou, Panayiotis A.,Barrett, Victoria J.,Biggadike, Keith,Butchers, Peter R.,Craven, Andrew,Ford, Alison J.,Guntrip, Stephen B.,Holmes, Duncan S.,Hughes, Sara C.,Jones, Anne E.,Looker, Brian E.,Mutch, Peter J.,Ruston, Mark,Needham, Deborah,Smith, Claire E.
, p. 159 - 170 (2014/02/14)
A series of novel, potent, and selective human β2 adrenoceptor agonists incorporating a sulfone moiety on the terminal right-hand-side phenyl ring of (R)-salmeterol is presented. Sulfone 10b had salmeterol-like potency and selectivity profile, long duration of action on guinea pig trachea, and longer than salmeterol duration of action in vivo, suitable for once-daily dosing. It had lower than salmeterol oral absorption in rat, lower bioavailability in rat and dog, and a high turnover in human hepatocytes. It was metabolized in human hepatocytes by hydroxylation, oxidation, cleavage, and conjugation; most of the metabolites would be expected to have reduced or no β2 activity. The 4-biphenylsulfonic acid was identified as a crystalline, non-hygroscopic salt of 10b, suitable for inhaled delivery. Furthermore, it was free of any genetic toxicity issues and was considered as a backup to vilanterol.
