Substituted 4-(2,2-diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters.
A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phosphodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models.
Frenette
Richard
R
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Québec, Canada. richard_frenette@merck.com
Blouin
Marc
M
Brideau
Christine
C
Chauret
Nathalie
N
Ducharme
Yves
Y
Friesen
Richard W
RW
Hamel
Pierre
P
Jones
Tom R
TR
Laliberté
France
F
Li
Chun
C
Masson
Paul
P
McAuliffe
Malia
M
Girard
Yves
Y
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000478:Alkylation; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000138:chemical synthesis / Q000494:pharmacology
D007202:Indicators and Reagents; C467607:L-791943; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4