Discovery of L-791,943: a potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor.
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.
Guay
Daniel
D
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Québec, Canada H9R 4P8. daniel_guay@merck.com
Hamel
Pierre
P
Blouin
Marc
M
Brideau
Christine
C
Chan
Chi Chung
CC
Chauret
Nathalie
N
Ducharme
Yves
Y
Huang
Zheng
Z
Girard
Mario
M
Jones
Tom R
TR
Laliberté
France
F
Masson
Paul
P
McAuliffe
Malia
M
Piechuta
Hanna
H
Silva
José
J
Young
Robert N
RN
Girard
Yves
Y
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
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