Discovery of L-791,943: A potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor

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.