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Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration

2009; Elsevier BV; Volume: 19; Issue: 17 Linguagem: Inglês

10.1016/j.bmcl.2009.04.012

1464-3405

Michael D. Woodrow, Stuart P. Ballantine, Michael D. Barker, Beth J. Clarke, John A. Dawson, Tony W. Dean, C. J. Delves, Brian Evans, Sharon L. Gough, Steven B. Guntrip, Stuart Holman, Duncan S. Holmes, Michael Kranz, Mika K. Lindvaal, Fiona S. Lucas, Margarete Neu, Lisa E. Ranshaw, Yemisi Solanke, Don O. Somers, Peter Ward, Joanne Wiseman,

Phenothiazines and Benzothiazines Synthesis and Activities

Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-α from isolated human peripheral blood mononuclear cells with a pIC50 of 11.1. GSK256066 also has a suitable profile for inhaled dosing.