Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10596243 | Bioorganic & Medicinal Chemistry Letters | 2013 | 7 Pages |
Abstract
(â)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration.
Keywords
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Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Koji Ochiai, Satoshi Takita, Akihiko Kojima, Tomohiko Eiraku, Kazuhiko Iwase, Tetsuya Kishi, Akira Ohinata, Yuichi Yageta, Tokutaro Yasue, David R. Adams, Yasushi Kohno,