title: Identification of 2,3-disubstituted pyridines as potent, orally active PDE4 inhibitors.
abstract: A series of 2,3-disubstituted pyridines were synthesized and evaluated for their PDE4 inhibitory activity. We successfully modified undesirable cyano group of initial lead compound 2 to 4-pyridyl group with improvement of in vitro efficacy and optimized the position of nitrogen atoms in pyridine moiety and alkylene linker. The most potent compound showed significant efficacy in animal models of asthma and inflammation.
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, Suita, Osaka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kato
authors.forename: Motoji
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nigo
authors.forename: Shunya
authors.initials: S
authors.lastname: Nakamura
authors.forename: Akira
authors.initials: A
authors.lastname: Fusano
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Teranishi
authors.forename: Mari N
authors.initials: MN
authors.lastname: Ito
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sumiyoshi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry* / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D058988:Phosphodiesterase 4 Inhibitors; D011725:Pyridines; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C023666:pyridine
keywords: 2,3-Disubstituted pyridine; Anti-inflammatory agent; PDE4 inhibitors; Phosphodiesterase 4; Structure–activity relationship