New quinoline-based PDE4 inhibitors through GSK-256066 fragment-based elaboration

We report here a new series of quinolines as PDE4 inhibitors obtained through fragment-based drug design methodologies on a fragment of GSK-256066 - i.e. a previously discovered lead compound, which was developed by GlaxoSmithKline. This approach led to the identification of several new and potent PDE4 inhibitors with IC50 values in the low nanomolar range (e.g. 5e with IC50 = 21.27 nM, 7e with IC50 = 33.47 nM and 5p with IC50 = 44.57 nM). In addition to the analysis of SARs, herein we report docking and molecular dynamics studies, performed to further assess how the variety of substituents introduced in selected positions of the quinoline scaffold influences the biological activity of the molecules.