Design and synthesis of inhaled p38 inhibitors for the treatment of chronic obstructive pulmonary disease

…, A Lemaitre, RA Lewthwaite, A Mahnke…

Index: Millan, David S.; Bunnage, Mark E.; Burrows, Jane L.; Butcher, Kenneth J.; Dodd, Peter G.; Evans, Timothy J.; Fairman, David A.; Hughes, Samantha J.; Kilty, Iain C.; Lemaitre, Arnaud; Lewthwaite, Russell A.; Mahnke, Axel; Mathias, John P.; Philip, James; Smith, Robert T.; Stefaniak, Mark H.; Yeadon, Michael; Phillips, Christopher Journal of Medicinal Chemistry, 2011 , vol. 54, # 22 p. 7797 - 7814

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Citation Number: 47

Abstract

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 “inhalation by design” 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 ...