title: Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity.
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. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo.
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., 2399-1 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ochiai
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takita
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Eiraku
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kojima
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Iwase
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kishi
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fukuchi
authors.forename: Tokutaro
authors.initials: T
authors.lastname: Yasue
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.forename: Robert W
authors.initials: RW
authors.lastname: Allcock
authors.forename: Zhong
authors.initials: Z
authors.lastname: Jiang
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kohno
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D058987:Phosphodiesterase 3 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001993:Bronchodilator Agents; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D011725:Pyridines