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

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

  • J Med Chem. 2011 Nov 24;54(22):7797-814. doi: 10.1021/jm200677b.
David S Millan 1 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
Affiliations

Affiliation

  • 1 Worldwide Medicinal Chemistry, Pfizer Global Research and Development , Sandwich Laboratories, Ramsgate Road, Sandwich, Kent, CT13 9NJ, U.K. david.millan@gmail.com
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 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-drug 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.

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