title: Phosphodiesterase inhibitors. Part 2: design, synthesis, and structure-activity relationships of dual PDE3/4-inhibitory pyrazolo[1,5-a]pyridines with anti-inflammatory and bronchodilatory activity.
abstract: A structural survey of pyrazolopyridine-pyridazinone phosphodiesterase (PDE) inhibitors was made with a view to optimization of their dual PDE3/4-inhibitory activity for respiratory disease applications. These studies identified (-)-6-(7-methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridine-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490, compound 2ac) as a compound with potent combined bronchodilatory and anti-inflammatory activity and an improved therapeutic window over roflumilast.
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: Naoki
authors.initials: N
authors.lastname: Ando
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: Akira
authors.initials: A
authors.lastname: Ohinata
authors.forename: Hitomi
authors.initials: H
authors.lastname: Zushi
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: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D015394:Molecular Structure; D058987:Phosphodiesterase 3 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001993:Bronchodilator Agents; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C447480:pyrazolo(3,4-b)pyridine; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4