Synthesis and biological activity of pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine derivatives as novel and potent phosphodiesterase type 4 inhibitors

A series of pyrido[3′,2′:4,5]furo[3,2-d]pyrimidines (PFP) were synthesized and tested for phosphodiesterase type 4 (PDE4) inhibitory activity, with the potential to treat asthma and chronic obstructive pulmonary disease (COPD). Structure–activity relationships within this series, leading to an increase of potency on the enzyme, is presented.Both gem-dimethylcyclohexyl moieties fused to the pyridine ring and the substitution at the 5 position of the PFP scaffold, proved to be key elements in order to get a high affinity in the enzyme.

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► Pyrido[3′,2′:4,5]furo[3,2-d]pyrimidines (PFP) is a new PDE4 inhibitor scaffold.
► 4-Amino-3,5-dichloropyridinyl at the 5 position is essential to get high activity.
► X-ray co-crystal structural analysis is a powerful tool in designing new molecules.
► Emesis and metabolism are the main issues in this series.