New Atglistatin closely related analogues: Synthesis and structure-activity relationship towards adipose triglyceride lipase inhibition

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DOIResolve DOI: http://doi.org/10.1016/j.ejmech.2016.04.021
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TypeArticle
Journal titleEuropean Journal of Medicinal Chemistry
ISSN0223-5234
Volume118
Pages290298
SubjectAdipose triglyceride lipase (ATGL); Atglistatin; Inhibitors; Structure–activity relationship; Lipolysis; Adipocytes
AbstractAdipose Triglyceride Lipase (ATGL) performs the first and rate-limiting step in lipolysis by hydrolyzing triacylglycerols stored in lipid droplets to diacylglycerols. By mediating lipolysis in adipose and non-adipose tissues, ATGL is a major regulator of overall energy metabolism and plasma lipid levels. Since chronically high levels of plasma lipids are linked to metabolic disorders including insulin resistance and type 2 diabetes, ATGL is an interesting therapeutic target. In the present study, fourteen closely related analogues of Atglistatin (1), a newly discovered ATGL inhibitor, were synthesized, and their ATGL inhibitory activity was evaluated. The effect of these analogues on lipolysis in 3T3-L1 adipocytes clearly shows that inhibition of the enzyme by Atglistatin (1) is due to the presence of the carbamate and N,N-dimethyl moieties on the biaryl central core at meta and para position, respectively. Mono carbamate-substituted analogue C2, in which the carbamate group was in the meta position as in Atglistatin (1), showed slight inhibition. Low dipole moment of Atglistatin (1) compared to the synthesized analogues possibly explains the lower inhibitory activities.
Publication date
PublisherElsevier
LanguageEnglish
AffiliationInformation and Communication Technologies; National Research Council Canada
Peer reviewedYes
IdentifierS0223523416303051
NPARC number23000316
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Record identifiereccc00fc-e795-47a9-8a8e-bbb8ef3256f5
Record created2016-07-06
Record modified2016-07-06
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