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-α 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.

Graphical abstractDiscovery of the potent and orally active PDE4 inhibitors 18 and 20 (PDE4A IC50 = 6 and 7 nM; HWB IC50 = 0.12 and 0.18 μM) is reported.Figure optionsDownload full-size imageDownload as PowerPoint slide