Abstract
An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT efficacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Cell Line
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Drug Evaluation, Preclinical
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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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Humans
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Hypoglycemic Agents / chemical synthesis
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Hypoglycemic Agents / chemistry*
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology*
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Liver / drug effects
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Liver / enzymology
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Mice
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Mice, Inbred C57BL
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Nicotinic Acids / chemical synthesis
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Nicotinic Acids / chemistry*
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Nicotinic Acids / pharmacokinetics
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Nicotinic Acids / pharmacology
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Rats
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Stearoyl-CoA Desaturase / antagonists & inhibitors*
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Stearoyl-CoA Desaturase / metabolism
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Structure-Activity Relationship
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Tissue Distribution
Substances
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Enzyme Inhibitors
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Hypoglycemic Agents
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Nicotinic Acids
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Stearoyl-CoA Desaturase