Design, synthesis, and biological evaluation of 8-biarylquinolines: a novel class of PDE4 inhibitors

Bioorg Med Chem Lett. 2008 Feb 15;18(4):1407-12. doi: 10.1016/j.bmcl.2008.01.004.

Michel Gallant ¹, Nathalie Chauret, David Claveau, Stephen Day, Denis Deschênes, Daniel Dubé, Zheng Huang, Patrick Lacombe, France Laliberté, Jean-François Lévesque, Susana Liu, Dwight Macdonald, Joseph Mancini, Paul Masson, Anthony Mastracchio, Donald Nicholson, Deborah A Nicoll-Griffith, Hélène Perrier, Myriam Salem, Angela Styhler, Robert N Young, Yves Girard

Affiliations

Affiliation

1 Merck Frosst Center for Therapeutic Research, Department of Medicinal Chemistry, PO Box 1005, Pointe Claire-Dorval, Que., Canada.

PMID: 18207397 DOI: 10.1016/j.bmcl.2008.01.004

Abstract

The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC(50)<10 nM) isozymes (A-D). In a human whole blood in vitro assay, they inhibit (IC(50)<0.5 microM) the LPS-induced release of the cytokine TNF-alpha. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.

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