Title of article :
Discovery of L-791,943: A potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor
Author/Authors :
Daniel Guay، نويسنده , , Pierre Hamel، نويسنده , , Marc Blouin، نويسنده , , Christine Brideau، نويسنده , , Chi-Chung Chan، نويسنده , , Nathalie Chauret، نويسنده , , Yves Ducharme، نويسنده , , Zheng Huang، نويسنده , , Mario Girard، نويسنده , , Tom R. Jones، نويسنده , , France Laliberté، نويسنده , , Paul Masson، نويسنده , , Malia McAuliffe، نويسنده , , Hanna Piechuta، نويسنده , , José Silva، نويسنده , , Robert N. Young، نويسنده , , Jean-Yves Girard، نويسنده ,
Abstract :
Structure–activity relationship studies directed toward improving the potency and metabolic stability of CDP-840 (3) resulted in the discovery of L-791,943 (11n) as a potent (HWB TNF-α=0.67 μM) and orally active phosphodiesterase type 4 (PDE4) inhibitor. This compound, which bears a stable bis-difluoromethoxy catechol and a pendant hexafluorocarbinol, exhibited a long half-life in rat and in squirrel monkey. It is well tolerated in ferret with an emetic threshold greater than 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig and in the ascaris-induced bronchoconstriction models in sheep and squirrel monkey.
