title: 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-alpha = 0.67 microM) 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.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Québec, Canada H9R 4P8. daniel_guay@merck.com
authors.forename: Daniel
authors.initials: D
authors.lastname: Guay
authors.forename: Pierre
authors.initials: P
authors.lastname: Hamel
authors.forename: Marc
authors.initials: M
authors.lastname: Blouin
authors.forename: Christine
authors.initials: C
authors.lastname: Brideau
authors.forename: Chi Chung
authors.initials: CC
authors.lastname: Chan
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
authors.forename: Mario
authors.initials: M
authors.lastname: Girard
authors.forename: Tom R
authors.initials: TR
authors.lastname: Jones
authors.forename: France
authors.initials: F
authors.lastname: Laliberté
authors.forename: Paul
authors.initials: P
authors.lastname: Masson
authors.forename: Malia
authors.initials: M
authors.lastname: McAuliffe
authors.forename: Hanna
authors.initials: H
authors.lastname: Piechuta
authors.forename: José
authors.initials: J
authors.lastname: Silva
authors.forename: Robert N
authors.initials: RN
authors.lastname: Young
authors.forename: Yves
authors.initials: Y
authors.lastname: Girard
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004639:Emetics / Q000494:pharmacology; D005289:Ferrets; D006168:Guinea Pigs; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D010047:Ovalbumin / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012453:Saimiri; D012756:Sheep; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004639:Emetics; C467607:L-791943; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4