Title of article :
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
Author/Authors :
Daniel Guay، نويسنده , , Louise Boulet، نويسنده , , Richard W. Friesen، نويسنده , , Mario Girard، نويسنده , , Pierre Hamel، نويسنده , , Zheng Huang، نويسنده , , France Laliberté، نويسنده , , Sébastien Laliberté، نويسنده , , Joseph A. Mancini، نويسنده , , Eric Muise، نويسنده , , Doug Pon، نويسنده , , Angela Styhler، نويسنده ,
Abstract :
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.
Keywords :
PDE4 , Type 4 phosphodiesterase , 8-Naphthyridin-4-one-3-carboxamides , COPD , MK-0873 , 1 , asthma
