title: Design, synthesis, and biological evaluation of 8-biarylquinolines: a novel class of PDE4 inhibitors.
abstract: The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC(50)<10 nM) isozymes (A-D). In a human whole blood in vitro assay, they inhibit (IC(50)<0.5 microM) the LPS-induced release of the cytokine TNF-alpha. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.
authors.affiliation: Merck Frosst Center for Therapeutic Research, Department of Medicinal Chemistry, PO Box 1005, Pointe Claire-Dorval, Que., Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Gallant
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: Zheng
authors.initials: Z
authors.lastname: Huang
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacombe
authors.forename: France
authors.initials: F
authors.lastname: Laliberté
authors.forename: Jean-François
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
authors.initials: J
authors.lastname: Mancini
authors.forename: Paul
authors.initials: P
authors.lastname: Masson
authors.forename: Anthony
authors.initials: A
authors.lastname: Mastracchio
authors.forename: Donald
authors.initials: D
authors.lastname: Nicholson
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nicoll-Griffith
authors.forename: Hélène
authors.initials: H
authors.lastname: Perrier
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
authors.forename: Yves
authors.initials: Y
authors.lastname: Girard
mesh_terms: D000818:Animals; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001713:Biphenyl Compounds; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011804:Quinolines