Document Detail


Inhibitors of mammalian acetyl-CoA carboxylase.
MedLine Citation:
PMID:  18221116     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Inhibition of acetyl-CoA carboxylase (ACC), with its resultant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect, in a concerted manner, a multitude of the cardiometabolic risk factors associated with diabetes, obesity, and the metabolic syndrome. Studies in ACC2 knockout mice and in experimental animals treated with isozyme-specific antisense oligonucleotides or with isozyme-nonselective ACC inhibitors have demonstrated the potential for treating metabolic syndrome through this modality. Co-crystallization of the biotin carboxylase and carboxyltransferase domains of eukaryotic ACC in the presence of substrates and inhibitors has revealed characteristics of the catalytic center that can be exploited in drug discovery. A variety of structurally diverse, mechanistically distinct classes of ACC inhibitors have been disclosed in the scientific and patent literature. Isozyme-nonselective ACC inhibitors may provide the optimal therapeutic potential. However, demonstration of the full potential of isozyme-selective inhibitors, once identified, should reveal advantages and liabilities associated with single isozyme inhibition.
Authors:
Jeffrey W Corbett; James H Harwood
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Recent patents on cardiovascular drug discovery     Volume:  2     ISSN:  1574-8901     ISO Abbreviation:  Recent Pat Cardiovasc Drug Discov     Publication Date:  2007 Nov 
Date Detail:
Created Date:  2008-01-28     Completed Date:  2008-02-25     Revised Date:  2011-11-10    
Medline Journal Info:
Nlm Unique ID:  101263805     Medline TA:  Recent Pat Cardiovasc Drug Discov     Country:  United Arab Emirates    
Other Details:
Languages:  eng     Pagination:  162-80     Citation Subset:  IM    
Affiliation:
Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. jeffrey.w.corbett@pfizer.com
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MeSH Terms
Descriptor/Qualifier:
Acetyl-CoA Carboxylase / antagonists & inhibitors*,  metabolism
Animals
Diabetes Mellitus / drug therapy,  enzymology
Drug Design
Enzyme Inhibitors / pharmacology*,  therapeutic use
Heart Diseases / drug therapy,  enzymology
Humans
Isoenzymes / antagonists & inhibitors,  metabolism
Metabolic Syndrome X / drug therapy,  enzymology
Mice
Obesity / drug therapy,  enzymology
Rats
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Isoenzymes; EC 6.4.1.2/Acetyl-CoA Carboxylase

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


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