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

Bioorganic & Medicinal Chemistry Letters
Michel GallantYves Girard

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.

References

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Jun 1, 2000·Biochemistry·F LalibertéZ Huang
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Citations

Apr 11, 2009·Chemical Communications : Chem Comm·Young-Shin KwakYugang Liu
Nov 20, 2012·Drug Discovery Today·Soumita Mukherjee, Manojit Pal
Nov 18, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·He TianGuilong Zhao
Oct 12, 2010·Bioorganic & Medicinal Chemistry Letters·Michel GallantYves Girard

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