Discovery of a rapidly metabolized, long-acting β(2) adrenergic receptor agonist with a short onset time incorporating a sulfone group suitable for once-daily dosing

Journal of Medicinal Chemistry
Panayiotis A ProcopiouClaire E Smith

Abstract

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.

References

Jan 1, 1993·Life Sciences·M JohnsonC J Whelan
Apr 1, 1993·Biopharmaceutics & Drug Disposition·T Trnovec, M Hrmová
Oct 6, 1997·American Journal of Respiratory and Critical Care Medicine·E HamelmannE W Gelfand
Mar 5, 1999·The European Respiratory Journal·J A BennettA E Tattersfield
Feb 16, 2008·Nature Reviews. Immunology·Stephen T Holgate, Riccardo Polosa
Jan 26, 2010·Bioorganic & Medicinal Chemistry Letters·Thierry BouyssouIngo Konetzki
Apr 21, 2010·Journal of Medicinal Chemistry·François BaurDaniel Wyss
Jan 15, 2011·British Journal of Pharmacology·Mario CazzolaMaria Gabriella Matera
Feb 1, 2011·Bioorganic & Medicinal Chemistry Letters·Daniel PérezCarles Puig
Jun 10, 2011·Bioorganic & Medicinal Chemistry Letters·Michael J StocksAlan Young
Jun 24, 2011·Bioorganic & Medicinal Chemistry·Panayiotis A ProcopiouGraham Somers
Jul 5, 2011·Bioorganic & Medicinal Chemistry Letters·Stephen ConnollyAlan Young
Sep 20, 2011·Bioorganic & Medicinal Chemistry·Panayiotis A ProcopiouGraham Somers
Dec 20, 2011·Bioorganic & Medicinal Chemistry Letters·John R JacobsenEdmund J Moran
May 23, 2012·Pharmacological Reviews·Mario CazzolaM Gabriella Matera
Aug 25, 2012·Expert Opinion on Investigational Drugs·Mario CazzolaMaria Gabriella Matera
Oct 9, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Andrew W HarrellRodger D Kempsford
Nov 8, 2012·The Journal of Pharmacology and Experimental Therapeutics·Robert J SlackRichard G Knowles
Apr 10, 2013·International Journal of Chronic Obstructive Pulmonary Disease·Rashmi MehtaGlenn Crater
Jul 19, 2013·Journal of Medicinal Chemistry·Marvin A Soriano-UrsúaSantiago Vilar

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Citations

Jan 25, 2017·Expert Opinion on Investigational Drugs·Mario MalerbaJaymin B Morjaria
Sep 17, 2014·Chemistry : a European Journal·Peng HeXiaoming Feng
Apr 14, 2015·Chemistry : a European Journal·Răzvan C CiocRomano V A Orru
Jun 6, 2014·ACS Medicinal Chemistry Letters·Michael J StocksAlan Young

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