(�)-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-dimethyl-pyrazolone subunit serves as an effective surrogate for the 5-methyl-4,5-dihydropyridazin-3(2H)-one ring of KCA-1490. The 2- and 7-substituents in the pyrazolo[1,5-a]pyridine subunit markedly influence the PDE-inhibitory profile. Moreover, a survey of bicyclic heteroaromatic replacements for the pyrazolo[1,5-a]pyridine allowed further refinement of the inhibitory profile and identified imidazo[1,2-a]pyridine-4,4-dimethylpyrazolone derivative as an orally active, achiral KCA-1490 analog with well-balanced dual PDE3/4-inhibitory activity. Figure 1. <img src='https://acs-archive-assets2.s3.amazonaws.com/241nm/uploads/76561_research_abstract_rxn.jpg' alt='' />

Design, synthesis, and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-4,4-dimethylpyrazolones

245th National Meeting (2013)

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