Author/Authors :
Michel Gallant، نويسنده , , Nathalie Chauret، نويسنده , , David Claveau، نويسنده , , Stephen Day، نويسنده , , Denis Deschênes، نويسنده , , Daniel Dubé، نويسنده , , Zheng Huang، نويسنده , , Patrick Lacombe، نويسنده , , France Laliberté، نويسنده , , Jean François Lévesque، نويسنده , , Susana Liu، نويسنده , , Dwight Macdonald، نويسنده , , Joseph Mancini، نويسنده , , Paul Masson، نويسنده , , Anthony Mastracchio، نويسنده , , Donald Nicholson، نويسنده , , Deborah A. Nicoll-Griffith، نويسنده , , Hélène Perrier، نويسنده , , Myriam Salem، نويسنده , , Angela Styhler، نويسنده , , et al.، نويسنده ,
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 (IC50 < 10 nM) isozymes (A–D). In a human whole blood in vitro assay, they inhibit (IC50 < 0.5 μM) the LPS-induced release of the cytokine TNF-α. 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.
Keywords :
Phosphodiesterases type 4 , inhibitors , Respiratory diseases , Emesis
