title: Phosphodiesterase inhibitors. Part 4: design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-4,4-dimethylpyrazolones.
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.
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: 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: 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: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D047069:Pyrazolones / Q000737:chemistry*; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C572644:4,4-dimethylpyrazolone; C576867:6-(7-methoxy-2-trifluoromethylpyrazolo(1,5-a)pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010726:Phosphodiesterase Inhibitors; D047069:Pyrazolones; D011724:Pyridazines; D011725:Pyridines; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4