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

• Published in: Bioorganic & medicinal chemistry letters 2012-09, Vol.22 (18), p.5833-5838
• Main Authors: Ochiai, Koji, Takita, Satoshi, Kojima, Akihiko, Eiraku, Tomohiko, Ando, Naoki, Iwase, Kazuhiko, Kishi, Tetsuya, Ohinata, Akira, Yageta, Yuichi, Yasue, Tokutaro, Adams, David R., Kohno, Yasushi
• Format: Article
• Language: English
• Subjects: anti-inflammatory activity; Asthma; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - chemistry; COPD; Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Dimethylpyrazolone; Dose-Response Relationship, Drug; Drug Design; Dual PDE3/4 inhibitor; Indexing in process; Medical sciences; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Pyrazolo[1,5-a]pyridine; Pyrazolones - chemistry; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacology; pyridines; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Stereoisomerism; Structure-Activity Relationship; structure-activity relationships; surveys
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.07.088

(–)-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(2H)-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-1H-pyrazol-5(4H)-one as an orally active, achiral KCA-1490 analog with well-balanced dual PDE3/4-inhibitory activity.