Bioorganic & Medicinal Chemistry Letters 2002-10-21

Substituted 4-(2,2-diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters.

Richard Frenette, Marc Blouin, Christine Brideau, Nathalie Chauret, Yves Ducharme, Richard W Friesen, Pierre Hamel, Tom R Jones, France Laliberté, Chun Li, Paul Masson, Malia McAuliffe, Yves Girard

Index: Bioorg. Med. Chem. Lett. 12(20) , 3009-13, (2002)

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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.