Phosphodiesterase inhibitors. Part 4: design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-4,4-dimethylpyrazolones.

Abstract (–)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5- a ]pyridin-4-yl)-5-methyl-4,5-dihydro-3-( 2H )-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. Here we show that a 4,4-dimethylpyrazolone subunit serves as an effective surrogate for the 5-methyl-4,5-dihydropyridazin-3(2 H )-one ring of KCA-1490 whilst lacking a stereogenic centre. The 2- and 7-substituents in the pyrazolo[1,5- a ]pyridine subunit markedly influence the PDE-inhibitory profile and can be adjusted to afford either potent PDE4-selective inhibitors or dual PDE3/4 inhibitors. A survey of bicyclic heteroaromatic replacements for the pyrazolo[1,5- a ]pyridine allowed further refinement of the inhibitory profile and identified 3-(8-methoxy-2-(trifluoromethyl)imidazo[1,2- a ]pyridin-5-yl)-4,4-dimethyl-1 H -pyrazol-5(4 H )-one as an orally active, achiral KCA-1490 analog with well-balanced dual PDE3/4-inhibitory activity.