Quinolines as a novel structural class of potent and selective PDE4 inhibitors: Optimisation for oral administration

Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD

A series of quinoline-3-carboxamides has been identified as potent inhibitors of PDE4. The SAR has been explored and these studies have highlighted compounds 43 and 48 which show good potency, selectivity and rat PK suitable for oral dosing. The crystal structure of an example quinoline bound into the active site of PDE4 is also described.Figure optionsDownload as PowerPoint slide