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.
Merck Frosst Center for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8. daniel_guay@merck.com
Daniel
D
Guay
Louise
L
Boulet
Richard W
RW
Friesen
Mario
M
Girard
Pierre
P
Hamel
Zheng
Z
Huang
France
F
Laliberté
Sébastien
S
Laliberté
Joseph A
JA
Mancini
Eric
E
Muise
Doug
D
Pon
Angela
A
Styhler
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