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

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.

Graphical abstractA series of quinoline-3-carboxamides has been identified as potent inhibitors of PDE4. The SAR has been explored and these studies have highlighted compound 4 which shows very high potency, selectivity and rat PK suitable for inhaled dosing. The crystal structure of exemplars from this series bound into the active site of PDE4 is also described.Figure optionsDownload full-size imageDownload as PowerPoint slide