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.
Guay
Daniel
D
Merck Frosst Center for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8. daniel_guay@merck.com
Boulet
Louise
L
Friesen
Richard W
RW
Girard
Mario
M
Hamel
Pierre
P
Huang
Zheng
Z
Laliberté
France
F
Laliberté
Sébastien
S
Mancini
Joseph A
JA
Muise
Eric
E
Pon
Doug
D
Styhler
Angela
A
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry*; D004285:Dogs; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000737:chemistry; D008956:Models, Chemical; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D012453:Saimiri; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D008070:Lipopolysaccharides; C532496:MK 0873; D009287:Naphthyridines; D014409:Tumor Necrosis Factor-alpha; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4