Abstract
In this study the first PDE4B selective inhibitor is described. Optimization of lead 2-arylpyrimidine derivatives afforded a series of potent PDE4B inhibitors with >100-fold selectivity over the PDE4D isozyme. With a good pharmacokinetic profile, a selected compound exhibited potent anti-inflammatory effects in vivo and showed less emesis compared with Cilomilast.
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemistry*
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Anti-Inflammatory Agents / pharmacokinetics
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Anti-Inflammatory Agents / pharmacology
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Area Under Curve
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
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Drug Discovery
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Humans
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Inhibitory Concentration 50
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Mice
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Phenylacetates / chemistry*
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Phenylacetates / pharmacokinetics
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Phenylacetates / pharmacology
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Phosphodiesterase 4 Inhibitors*
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Phosphodiesterase Inhibitors / chemistry*
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Phosphodiesterase Inhibitors / pharmacokinetics
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Phosphodiesterase Inhibitors / pharmacology
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Pyrimidines / chemistry*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Structure-Activity Relationship
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Thiophenes / chemistry*
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Thiophenes / pharmacokinetics
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Thiophenes / pharmacology
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Tumor Necrosis Factor-alpha / biosynthesis
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Vomiting / chemically induced
Substances
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2-(4-((2-(5-chlorothiophen-2-yl)-5-ethyl-6-methylpyrimidin-4-yl)amino)phenyl)acetic acid
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Anti-Inflammatory Agents
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Phenylacetates
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Phosphodiesterase 4 Inhibitors
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Phosphodiesterase Inhibitors
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Pyrimidines
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Thiophenes
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Tumor Necrosis Factor-alpha
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Cyclic Nucleotide Phosphodiesterases, Type 4
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PDE4B protein, human
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PDE4D protein, mouse