Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: structure-activity relationship, optimization, and identification of a highly potent, well tolerated, PDE4 inhibitor.

Dwight Macdonald, Anthony Mastracchio, Hélène Perrier, Daniel Dubé, Michel Gallant, Patrick Lacombe, Denis Deschênes, Bruno Roy, John Scheigetz, Kevin Bateman, Chun Li, Laird A Trimble, Stephen Day, Nathalie Chauret, Deborah A Nicoll-Griffith, Jose M Silva, Zheng Huang, France Laliberté, Susana Liu, Diane Ethier, Doug Pon, Eric Muise, Louise Boulet, Chi Chung Chan, Angela Styhler, Stella Charleson, Joseph Mancini, Paul Masson, David Claveau, Donald Nicholson, Mervyn Turner, Robert N Young, Yves Girard

Index: Bioorg. Med. Chem. Lett. 15(23) , 5241-6, (2005)

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Abstract

The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.