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Structure-activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL).

ABSTRACT: Adipose triglyceride lipase (ATGL) catalyzes the degradation of cellular triacylglycerol stores and strongly determines the concentration of circulating fatty acids (FAs). High serum FA levels are causally linked to the development of insulin resistance and impaired glucose tolerance, which eventually progresses to overt type 2 diabetes. ATGL-specific inhibitors could be used to lower circulating FAs, which can counteract the development of insulin resistance. In this article, we report about structure-activity relationship (SAR) studies of small molecule inhibitors of ATGL based on a hydrazone chemotype. The SAR indicated that the binding pocket of ATGL requests rather linear compounds without bulky substituents. The best inhibitor showed an IC50=10?M in an assay with COS7-cell lysate overexpressing murine ATGL.

SUBMITTER: Mayer N

PROVIDER: S-EPMC4457358 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Structure-activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL).

Mayer Nicole N Schweiger Martina M Melcher Michaela-Christina MC Fledelius Christian C Zechner Rudolf R Zimmermann Robert R Breinbauer Rolf R

Bioorganic & medicinal chemistry 20150305 12

Adipose triglyceride lipase (ATGL) catalyzes the degradation of cellular triacylglycerol stores and strongly determines the concentration of circulating fatty acids (FAs). High serum FA levels are causally linked to the development of insulin resistance and impaired glucose tolerance, which eventually progresses to overt type 2 diabetes. ATGL-specific inhibitors could be used to lower circulating FAs, which can counteract the development of insulin resistance. In this article, we report about st ...[more]

PMID: 25778769

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