Inhalation by Design: Novel Tertiary Amine Muscarinic M3 Receptor Antagonists with Slow Off-Rate Binding Kinetics for Inhaled Once-Daily Treatment of Chronic Obstructive Pulmonary Disease

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• 作者：Paul A. Glossop ; Christine A. L. Watson ; David A. Price ; Mark E. Bunnage ; Donald S. Middleton ; Anthony Wood ; Kim James ; Dannielle Roberts ; Ross S. Strang ; Michael Yeadon ; Christelle Perros-Huguet ; Nicholas P. Clarke ; Michael A. Trevethick ; Ian Machin ; Emilio F. Stuart ; Steven M. Evans ; Anthony C. Harrison ; David A. Fairman ; Balaji Agoram ; Jane L. Burrows ; Neil Feeder ; Craig K. Fulton ; Barry R. Dillon ; David A. Entwistle ; Fiona J. Spence
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 13, 2011
• 年：2011
• 卷：54
• 期：19
• 页码：6888-6904
• 全文大小：1301K
• 年卷期：v.54,no.19(October 13, 2011)
• ISSN：1520-4804

文摘

A novel tertiary amine series of potent muscarinic M₃ receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M₃ receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug鈥揹rug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.