The synthesis and biological evaluation of a novel series of indole PDE4 inhibitors I

This communication describes the synthesis and in vitro evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds described contain an indole moiety which replaces the ‘rolipram-like’ 3-methoxy-4-cyclopentoxy motif. Several of the compounds presented possess low nanomolar IC 50's for PDEIV inhibition. In vivo activities determined from measurement of serum TNF-α levels in LPS challenged mice (mouse endotoxemia model) are also reported. The synthesis, in vitro and in vivo evaluation of a novel potent series of indole phosphodiesterase type (IV) (PDE4) inhibitors 1 is presented. Several of the indoles presented possess low nanomolar IC 50's for PDE4 inhibition. The results demonstrate that the indole is an effective isostere for the 3-methoxy 4-cyclopentoxy motif commonly observed in ‘rolipram-like’ PDE4 inhibitors.