Synthesis and Structure−Activity Relationships of Long-acting β2 Adrenergic Receptor Agonists Incorporating Metabolic Inactivation: An Antedrug Approach

详细信息    查看全文

• 作者：Panayiotis A. Procopiou ; Victoria J. Barrett ; Nicola J. Bevan ; Keith Biggadike ; Philip C. Box ; Peter R. Butchers ; Diane M. Coe ; Richard Conroy ; Amanda Emmons ; Alison J. Ford ; Duncan S. Holmes ; Helen H
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：June 10, 2010
• 年：2010
• 卷：53
• 期：11
• 页码：4522-4530
• 全文大小：887K
• 年卷期：v.53,no.11(June 10, 2010)
• ISSN：1520-4804

文摘

A series of saligenin β₂ 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 β₂, β₁, and β₃ 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 β₂-receptor is presented.