Abstract
HSL inhibition is a promising approach to the treatment of dyslipidemia. As a result of re-optimization of lead compound 2, we identified novel compound 25a exhibiting potent inhibitory activity against HSL enzyme and cell with high selectivity for cholinesterases (AChE and BuChE). Reflecting its potent in vitro activity, compound 25a exhibited antilipolytic effect in rats at 1mg/kg p.o., which indicated that this novel compound is the most potent orally active HSL inhibitor. Moreover, compound 25a did not show bioactivation liability.
Keywords:
Boronic acid; Dyslipidemia; Hormone sensitive lipase (HSL); Lipolysis.
Copyright © 2017 Elsevier Ltd. All rights reserved.
MeSH terms
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Acetylcholinesterase / chemistry
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Acetylcholinesterase / metabolism
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Administration, Oral
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Animals
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Butyrylcholinesterase / chemistry
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Butyrylcholinesterase / metabolism
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Drug Design*
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Enzyme Activation / drug effects
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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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Enzyme Inhibitors / pharmacology
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Glutathione / chemistry
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Glutathione / metabolism
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Glycerol / blood
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Half-Life
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Humans
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Hypolipidemic Agents / chemical synthesis*
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Hypolipidemic Agents / chemistry
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Hypolipidemic Agents / pharmacokinetics
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Hypolipidemic Agents / pharmacology*
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Inhibitory Concentration 50
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Male
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Rats
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Rats, Wistar
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / chemistry
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Recombinant Proteins / isolation & purification
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Sterol Esterase / antagonists & inhibitors*
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Sterol Esterase / genetics
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Sterol Esterase / metabolism
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Hypolipidemic Agents
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Recombinant Proteins
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Sterol Esterase
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Acetylcholinesterase
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Butyrylcholinesterase
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Glutathione
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Glycerol