Abstract
Spirocyclic secondary amine-derived trisubstituted ureas were identified as highly potent, bioavailable and selective soluble epoxide hydrolase (sEH) inhibitors. Despite good oral exposure and excellent ex vivo target engagement in blood, one such compound, rac-1a, failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This study posed the question as to whether sEH inhibition provides a robust mechanism leading to a significant antihypertensive effect.
MeSH terms
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Amines / chemistry*
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Animals
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Antihypertensive Agents / chemical synthesis*
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Antihypertensive Agents / chemistry
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Antihypertensive Agents / pharmacokinetics
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Cell Line
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Drug Discovery
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Epoxide Hydrolases / antagonists & inhibitors*
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Epoxide Hydrolases / metabolism
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Humans
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Rats
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Rats, Inbred SHR
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Spiro Compounds / chemistry*
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Structure-Activity Relationship
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Urea / analogs & derivatives*
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Urea / chemical synthesis
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Urea / pharmacokinetics
Substances
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Amines
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Antihypertensive Agents
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Enzyme Inhibitors
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Spiro Compounds
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Urea
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Epoxide Hydrolases