title: Substituted aminopyridines as potent and selective phosphodiesterase-4 inhibitors.
abstract: 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).
authors.affiliation: Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Québec, Canada H9R 4P8. bernard_cote@merck.com
authors.forename: Bernard
authors.initials: B
authors.lastname: Côté
authors.forename: Richard
authors.initials: R
authors.lastname: Frenette
authors.forename: Sylvie
authors.initials: S
authors.lastname: Prescott
authors.forename: Marc
authors.initials: M
authors.lastname: Blouin
authors.forename: Christine
authors.initials: C
authors.lastname: Brideau
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
authors.forename: Richard W
authors.initials: RW
authors.lastname: Friesen
authors.forename: France
authors.initials: F
authors.lastname: Laliberté
authors.forename: Paul
authors.initials: P
authors.lastname: Masson
authors.forename: Angela
authors.initials: A
authors.lastname: Styhler
authors.forename: Yves
authors.initials: Y
authors.lastname: Girard
mesh_terms: 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
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4