Substituted aminopyridines as potent and selective phosphodiesterase-4 inhibitors.
The synthesis and the biological evaluation of new potent phosphodiesterase type 4 (PDE4) inhibitors are presented. This new series was elaborated by replacement of the metabolically resistant phenyl hexafluorocarbinol of L-791,943 (1) by a substituted aminopyridine residue. The structure-activity relationship of N-substitution on 3 led to the identification of (-)-3n which exhibited a good PDE4 inhibitor activity (HWB-TNFalpha=0.12 microM) and an improved pharmacokinetic profile over L-791,943 (rat t(1/2)=2 h). (-)-3n was well tolerated in ferret with an emetic threshold of 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig (54%, 0.1 mg/kg, ip) as well as the ascaris-induced bronchoconstriction model in sheep (64%/97%, early/late, 0.5 mg/kg, iv).
Côté
Bernard
B
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Québec, Canada H9R 4P8. bernard_cote@merck.com
Frenette
Richard
R
Prescott
Sylvie
S
Blouin
Marc
M
Brideau
Christine
C
Ducharme
Yves
Y
Friesen
Richard W
RW
Laliberté
France
F
Masson
Paul
P
Styhler
Angela
A
Girard
Yves
Y
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005289:Ferrets; D006168:Guinea Pigs; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D051381:Rats; D012756:Sheep; D013329:Structure-Activity Relationship; D013810:Therapeutic Equivalency; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014839:Vomiting / Q000139:chemically induced
D000631:Aminopyridines; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4