Inhalation by Design: Novel Ultra-Long-Acting β2-Adrenoreceptor Agonists for Inhaled Once-Daily Treatment of Asthma and Chronic Obstructive Pulmonary Disease That Utilize a Sulfonamide

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• 作者：Paul A. Glossop ; Charlotte A. L. Lane ; David A. Price ; Mark E. Bunnage ; Russell A. Lewthwaite ; Kim James ; Alan D. Brown ; Michael Yeadon ; Christelle Perros-Huguet ; Michael A. Trevethick ; Nicholas P. Cl
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：September 23, 2010
• 年：2010
• 卷：53
• 期：18
• 页码：6640-6652
• 全文大小：1136K
• 年卷期：v.53,no.18(September 23, 2010)
• ISSN：1520-4804

文摘

A novel series of potent and selective sulfonamide derived β₂-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.