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

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

Bioorganic & medicinal chemistry letters (2009-08-07)

Michael D Woodrow, Stuart P Ballantine, Michael D Barker, Beth J Clarke, John Dawson, Tony W Dean, Christopher 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 E Solanke, Don O Somers, Peter Ward, Joanne O Wiseman

PMID19656678

摘要

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-alpha from isolated human peripheral blood mononuclear cells with a pIC(50) of 11.1. GSK256066 also has a suitable profile for inhaled dosing.