Design and Synthesis of Inhaled p38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease

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• 作者：David S. Millan ; Mark E. Bunnage ; Jane L. Burrows ; Kenneth J. Butcher ; Peter G. Dodd ; Timothy J. Evans ; David A. Fairman ; Samantha J. Hughes ; Iain C. Kilty ; Arnaud Lemaitre ; Russell A. Lewthwaite ; Axel Mahnke ; John P. Mathias ; James Philip ; Robert T. Smith ; Mark H. Stefaniak ; Michael Yeadon ; Christopher Phillips
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 24, 2011
• 年：2011
• 卷：54
• 期：22
• 页码：7797-7814
• 全文大小：1433K
• 年卷期：v.54,no.22(November 24, 2011)
• ISSN：1520-4804

文摘

This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and 鈥渋nhalation by design鈥?principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been designed to be potent and selective for p38, with an emphasis on slow enzyme dissociation kinetics to deliver prolonged lung p38 inhibition. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimize systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance and glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimize drug鈥揹rug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity, and solubility were considered to ensure compatibility with a dry powder inhaler. 1ab (PF-03715455) was subsequently identified as a clinical candidate from this series with efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of COPD.