title: Substituted 4-(2,2-diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters.
abstract: 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.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Québec, Canada. richard_frenette@merck.com
authors.forename: Richard
authors.initials: R
authors.lastname: Frenette
authors.forename: Marc
authors.initials: M
authors.lastname: Blouin
authors.forename: Christine
authors.initials: C
authors.lastname: Brideau
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
authors.forename: Richard W
authors.initials: RW
authors.lastname: Friesen
authors.forename: Pierre
authors.initials: P
authors.lastname: Hamel
authors.forename: Tom R
authors.initials: TR
authors.lastname: Jones
authors.forename: France
authors.initials: F
authors.lastname: Laliberté
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.forename: Paul
authors.initials: P
authors.lastname: Masson
authors.forename: Malia
authors.initials: M
authors.lastname: McAuliffe
authors.forename: Yves
authors.initials: Y
authors.lastname: Girard
mesh_terms: 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
chemical_list: 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