Optimization and structure-activity relationship of a series of 1-phenyl-1,8-naphthyridin-4-one-3-carboxamides: identification of MK-0873, a potent and effective PDE4 inhibitor.

A SAR study of a series of 1-phenyl-1,8-naphthyridin-4-one-3-carboxamides is described. Optimization of the series was based on in vitro potency against PDE4, inhibition of the LPS-induced production of TNF-alpha in human whole blood and minimizing affinity for the hERG potassium channel. From these studies, compounds 18 and 20 (MK-0873) were identified as optimized PDE4 inhibitors with good overall in vitro and in vivo profiles and selected as development candidates.

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 (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.