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

Koji Ochiai; Satoshi Takita; Akihiko Kojima; Tomohiko Eiraku; Naoki Ando; Kazuhiko Iwase; Tetsuya Kishi; Akira Ohinata; Yuichi Yageta; Tokutaro Yasue; David R Adams; Yasushi Kohno

doi:10.1016/j.bmcl.2012.07.088

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

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5833-8. doi: 10.1016/j.bmcl.2012.07.088. Epub 2012 Jul 31.

Authors

Koji Ochiai¹, Satoshi Takita, Akihiko Kojima, Tomohiko Eiraku, Naoki Ando, Kazuhiko Iwase, Tetsuya Kishi, Akira Ohinata, Yuichi Yageta, Tokutaro Yasue, David R Adams, Yasushi Kohno

Affiliation

¹ Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.

PMID: 22884989
DOI: 10.1016/j.bmcl.2012.07.088

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(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.

MeSH terms

Bridged Bicyclo Compounds, Heterocyclic / chemistry*
Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
Dose-Response Relationship, Drug
Drug Design*
Models, Molecular
Molecular Structure
Phosphodiesterase Inhibitors / chemical synthesis*
Phosphodiesterase Inhibitors / chemistry
Phosphodiesterase Inhibitors / pharmacology*
Pyrazolones / chemistry*
Pyridazines / chemical synthesis
Pyridazines / chemistry
Pyridazines / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Stereoisomerism
Structure-Activity Relationship

Substances

4,4-dimethylpyrazolone
6-(7-methoxy-2-trifluoromethylpyrazolo(1,5-a)pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone
Bridged Bicyclo Compounds, Heterocyclic
Phosphodiesterase Inhibitors
Pyrazolones
Pyridazines
Pyridines
Cyclic Nucleotide Phosphodiesterases, Type 3
Cyclic Nucleotide Phosphodiesterases, Type 4