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-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.
MeSH terms
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Animals
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Chemistry, Pharmaceutical / methods*
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Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry*
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Dogs
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Drug Design
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / chemistry
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Humans
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Inhibitory Concentration 50
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Lipopolysaccharides / chemistry
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Models, Chemical
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Naphthyridines / chemical synthesis*
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Naphthyridines / pharmacology
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Protein Binding
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Rats
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Saimiri
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Tumor Necrosis Factor-alpha / metabolism
Substances
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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Lipopolysaccharides
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MK 0873
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Naphthyridines
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Tumor Necrosis Factor-alpha
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Cyclic Nucleotide Phosphodiesterases, Type 4