title: Phosphodiesterase inhibitors. Part 5: hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration.
abstract: (-)-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.
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ochiai
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takita
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kojima
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Eiraku
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Iwase
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kishi
authors.forename: Akira
authors.initials: A
authors.lastname: Ohinata
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yageta
authors.forename: Tokutaro
authors.initials: T
authors.lastname: Yasue
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kohno
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D001993:Bronchodilator Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000737:chemistry / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D007962:Leukocytes / Q000187:drug effects; D058987:Phosphodiesterase 3 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011724:Pyridazines / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C576867:6-(7-methoxy-2-trifluoromethylpyrazolo(1,5-a)pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D011724:Pyridazines; D011725:Pyridines; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4