title: Alkyl-bridged substituted 8-arylquinolines as highly potent PDE IV inhibitors.
abstract: Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-454560. The pharmacokinetic profile of the best analogs and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
authors.affiliation: Merck Frosst Center for Therapeutic Research, Pointe Claire-Dorval, Québec, Canada. patrick_lacombe@merck.com
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacombe
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.forename: David
authors.initials: D
authors.lastname: Claveau
authors.forename: Stephen
authors.initials: S
authors.lastname: Day
authors.forename: Denis
authors.initials: D
authors.lastname: Deschênes
authors.forename: Daniel
authors.initials: D
authors.lastname: Dubé
authors.forename: Michel
authors.initials: M
authors.lastname: Gallant
authors.forename: Yves
authors.initials: Y
authors.lastname: Girard
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
authors.forename: France
authors.initials: F
authors.lastname: Laliberté
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Lévesque
authors.forename: Susana
authors.initials: S
authors.lastname: Liu
authors.forename: Dwight
authors.initials: D
authors.lastname: Macdonald
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Mancini
authors.forename: Paul
authors.initials: P
authors.lastname: Masson
authors.forename: Donald W
authors.initials: DW
authors.lastname: Nicholson
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nicoll-Griffith
authors.forename: Myriam
authors.initials: M
authors.lastname: Salem
authors.forename: Angela
authors.initials: A
authors.lastname: Styhler
authors.forename: Robert N
authors.initials: RN
authors.lastname: Young
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D006168:Guinea Pigs; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D010047:Ovalbumin / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D012453:Saimiri; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D010047:Ovalbumin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4