Heterocyclic-fused 3(2H)-pyridazinones as potent and selective PDE IV inhibitors: Further structure-activity relationships and molecular modelling studies

Article abstract of DOI:10.1016/S0223-5234(99)80030-0

A novel group of heterocyclic-fused 3(2H)-pyridazinones were synthesized and evaluated as PDE III and PDE IV inhibitors and their affinity for ³H Rolipram high affinity binding site was determined. The obtained data demonstrated that some of the new compounds are endowed with potent and selective PDE IV inhibitory activity and greatly attenuated affinity for the Rolipram high affinity binding site that seems to be responsible for unwanted effects. Theoretical calculations, performed on representative compounds, demonstrated the presence of three hydrogen-bonding acceptor regions, of which one looks quite different with respect to literature compounds. This finding could explain the different pharmacological profile of the title compounds with respect to the analogs reported in the literature.