Document Detail


Plasma-based approach to measure target engagement for liver-targeting stearoyl-CoA desaturase 1 inhibitors.
MedLine Citation:
PMID:  21642745     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A positive correlation between stearoyl-CoA desaturase (SCD)1 expression and metabolic diseases has been reported in rodents and humans. These findings indicate that SCD1 is a promising therapeutic target for the chronic treatment of diabetes and dyslipidemia. The SCD1 enzyme is expressed at high levels in several human tissues and is required for the biosynthesis of monounsaturated fatty acids, which are involved in many biological processes. Liver-targeted SCD inhibitors were designed to pharmacologically manipulate SCD1 activity in the liver to avoid adverse events due to systemic inhibition. This article describes the development of a plasma-based SCD assay to assess the level of SCD inhibition, which is defined in this article as target engagement. Essentially, animals are dosed with an exogenous deuterated tracer (d7-stearic acid) as substrate, and the converted d7-oleic acid product is measured to monitor SCD1 inhibition. This study reveals that this plasma-based assay correlates with liver SCD1 inhibition and can thus have clinical utility.
Authors:
France Landry; Chi-Chung Chan; Zheng Huang; Gregoire Leclair; Chun Sing Li; Renata Oballa; Lei Zhang; Kevin Bateman
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Publication Detail:
Type:  Journal Article     Date:  2011-06-05
Journal Detail:
Title:  Journal of lipid research     Volume:  52     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-18     Completed Date:  2011-11-08     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1494-9     Citation Subset:  IM    
Affiliation:
Merck Frosst Canada Ltd., Kirkland, Quebec, Canada. france_landry@sympatico.ca
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MeSH Terms
Descriptor/Qualifier:
Acetates* / administration & dosage,  pharmacokinetics
Animals
Biological Assay / methods*
Carbon Radioisotopes / analysis
Chromatography, High Pressure Liquid
Deuterium / analysis
Diabetes Mellitus / blood*,  drug therapy,  physiopathology
Dyslipidemias / blood*,  drug therapy,  physiopathology
Enzyme Inhibitors / administration & dosage,  pharmacokinetics
Humans
Liver / metabolism*
Male
Mass Spectrometry
Molecular Targeted Therapy / methods
Oleic Acid / analysis*,  metabolism
Plasma / chemistry,  metabolism
Rats
Rats, Sprague-Dawley
Stearoyl-CoA Desaturase / antagonists & inhibitors*,  metabolism
Tetrazoles* / administration & dosage,  pharmacokinetics
Chemical
Reg. No./Substance:
0/(5-(3-(4-(2-bromo-5-fluorophenoxy)piperidin-1-yl)isoxazol-5-yl)-2H-tetrazol-2-yl)acetic acid; 0/Acetates; 0/Carbon Radioisotopes; 0/Enzyme Inhibitors; 0/Tetrazoles; 112-80-1/Oleic Acid; 7782-39-0/Deuterium; EC 1.14.19.1/Stearoyl-CoA Desaturase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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