ABSTRACT
This chapter discusses the medicinal chemistry of selective small-molecule PDE4 inhibitors with a focus on those inhibitors that have reached the clinic. Any discussion of the medicinal chemistry of phosphodiesterases 4 (PDE4) inhibitors has to begin with rolipram, the key prototypical PDE4 inhibitor, because of the large number of programs that have used its key pharmacophore in their design and discovery strategies. Hypothesis within the PDE4 area is that inhibition of phosphodiesterase 4D is responsible for the widespread emetic effects seen with PDE4 inhibitors. Medicinal chemists had the good fortune during the investigation of the structure–activity relationship of rolipram to be able to approach it in modular fashion. Rolipram’s clinical withdrawal, numerous clinical studies have been conducted with selective PDE4 inhibitors but, as yet, none of these selective PDE4 inhibitors have reached the marketplace.
