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

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 (IC50 < 1 nM) and also of LPS-induced TNF-α release in human whole blood (IC50 < 0.5 μM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC50 < 0.1 mg/kg ip) but require a dose of about 10 mg/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.

Graphical abstractThe discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are described. From this series of compounds, the development candidate L-454,560 was selected.Figure optionsDownload full-size imageDownload as PowerPoint slide