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

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• 作者：Panayiotis A. Procopiou ; Victoria J. Barrett ; Keith Biggadike ; Peter R. Butchers ; Andrew Craven ; Alison J. Ford ; Stephen B. Guntrip ; Duncan S. Holmes ; Sara C. Hughes ; Anne E. Jones ; Brian E. Looker ; Peter J. Mutch ; Mark Ruston ; Deborah Needham ; Claire E. Smith
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：January 9, 2014
• 年：2014
• 卷：57
• 期：1
• 页码：159-170
• 全文大小：525K
• ISSN：1520-4804

文摘

A series of novel, potent, and selective human 尾₂ 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 尾₂ 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.