Phosphodiesterase inhibitors. Part 2: Design, synthesis, and structure–activity relationships of dual PDE3/4-inhibitory pyrazolo[1,5-a]pyridines with anti-inflammatory and bronchodilatory activity

Abstract A structural survey of pyrazolopyridine-pyridazinone phosphodiesterase (PDE) inhibitors was made with a view to optimization of their dual PDE3/4-inhibitory activity for respiratory disease applications. These studies identified (−)-6-(7-methoxy-2-trifluoromethylpyrazolo[1,5- a ]pyridine-4-yl)-5-methyl-4,5-dihydro-3-(2 H )-pyridazinone (KCA-1490, compound 2ac ) as a compound with potent combined bronchodilatory and anti-inflammatory activity and an improved therapeutic window over roflumilast.