Abstract
A series of potent nicotinamide inhibitors of soluble epoxides hydrolase (sEH) is disclosed. This series was designed using structure-based deconstruction and a combination of two HTS hit series, resulting in hybrid analogs that retained the optimal potency from one series, and acceptable in vitro metabolic stability from the other. Structure-guided optimization of these analogs gave rise to nanomolar inhibitors of human sEH that had acceptable plasma exposure to qualify them as probes to determine the in vivo phenotypic consequences of sEH inhibition.
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemical synthesis*
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology
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Binding Sites
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Cell Line, Tumor
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Crystallography, X-Ray
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Epoxide Hydrolases / antagonists & inhibitors*
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Epoxide Hydrolases / metabolism
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Humans
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Microsomes, Liver / metabolism
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Niacinamide / chemical synthesis*
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Niacinamide / chemistry
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Niacinamide / pharmacology
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Rats
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Structure-Activity Relationship
Substances
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Anti-Inflammatory Agents
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Enzyme Inhibitors
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Niacinamide
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Epoxide Hydrolases