Substituted 2-pyridinemethanol derivatives as potent and selective phosphodiesterase-4 inhibitors.
The synthesis and the phosphodiesterase-4 (PDE4) inhibitory activity of 2-pyridinemethanol derivatives is described. The evaluation of the structure-activity relationship (SAR) in this series of novel PDE4 inhibitors led to the identification of compound 9 which exhibits excellent in vitro activity, desirable pharmacokinetic parameters and good efficacy in animal models of bronchoconstriction.
Ducharme
Yves
Y
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8. yves_ducharme@merck.com
Friesen
Richard W
RW
Blouin
Marc
M
Côté
Bernard
B
Dubé
Daniel
D
Ethier
Diane
D
Frenette
Richard
R
Laliberté
France
F
Mancini
Joseph A
JA
Masson
Paul
P
Styhler
Angela
A
Young
Robert N
RN
Girard
Yves
Y
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010847:Picolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012453:Saimiri; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D010726:Phosphodiesterase Inhibitors; D010847:Picolines; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4