Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL)

Nicole Mayer; Martina Schweiger; Elisabeth Fuchs; Anna K. Migglautsch; Carina Doler; Gernot F. Grabner; Matthias Romauch,; Michaela Christina Melcher; Rudolf Zechner; Robert Zimmermann; Rolf Breinbauer

doi:10.1016/j.bmc.2020.115610

Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL)

Nicole Mayer, Martina Schweiger, Elisabeth Fuchs, Anna K. Migglautsch, Carina Doler, Gernot F. Grabner, Matthias Romauch,, Michaela Christina Melcher, Rudolf Zechner, Robert Zimmermann, Rolf Breinbauer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

High serum fatty acid (FA) levels are causally linked to the development of insulin resistance, which eventually progresses to type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) generalized in the term metabolic syndrome. Adipose triglyceride lipase (ATGL) is the initial enzyme in the hydrolysis of intracellular triacylglycerol (TG) stores, liberating fatty acids that are released from adipocytes into the circulation. Hence, ATGL-specific inhibitors have the potential to lower circulating FA concentrations, and counteract the development of insulin resistance and NAFLD. In this article, we report about structure–activity relationship (SAR) studies of small molecule inhibitors of murine ATGL which led to the development of Atglistatin. Atglistatin is a specific inhibitor of murine ATGL, which has proven useful for the validation of ATGL as a potential drug target.

Original language	English
Article number	115610
Journal	Bioorganic and Medicinal Chemistry
Volume	28
Issue number	16
DOIs	https://doi.org/10.1016/j.bmc.2020.115610
Publication status	Published - 15 Aug 2020

Keywords

Atglistatin
Lipolysis
NAFLD
PNPLA2
Small molecule inhibitor

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Fields of Expertise

Human- & Biotechnology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bmc.2020.115610

Cite this

Mayer, N., Schweiger, M., Fuchs, E., Migglautsch, A. K., Doler, C., Grabner, G. F., Romauch, M., Melcher, M. C., Zechner, R., Zimmermann, R., & Breinbauer, R. (2020). Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL). Bioorganic and Medicinal Chemistry, 28(16), Article 115610. https://doi.org/10.1016/j.bmc.2020.115610

Mayer, N, Schweiger, M, Fuchs, E, Migglautsch, AK, Doler, C, Grabner, GF, Romauch, M, Melcher, MC, Zechner, R, Zimmermann, R & Breinbauer, R 2020, 'Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL)', Bioorganic and Medicinal Chemistry, vol. 28, no. 16, 115610. https://doi.org/10.1016/j.bmc.2020.115610

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title = "Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL)",

abstract = "High serum fatty acid (FA) levels are causally linked to the development of insulin resistance, which eventually progresses to type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) generalized in the term metabolic syndrome. Adipose triglyceride lipase (ATGL) is the initial enzyme in the hydrolysis of intracellular triacylglycerol (TG) stores, liberating fatty acids that are released from adipocytes into the circulation. Hence, ATGL-specific inhibitors have the potential to lower circulating FA concentrations, and counteract the development of insulin resistance and NAFLD. In this article, we report about structure–activity relationship (SAR) studies of small molecule inhibitors of murine ATGL which led to the development of Atglistatin. Atglistatin is a specific inhibitor of murine ATGL, which has proven useful for the validation of ATGL as a potential drug target.",

keywords = "Atglistatin, Lipolysis, NAFLD, PNPLA2, Small molecule inhibitor",

author = "Nicole Mayer and Martina Schweiger and Elisabeth Fuchs and Migglautsch, {Anna K.} and Carina Doler and Grabner, {Gernot F.} and Matthias Romauch, and Melcher, {Michaela Christina} and Rudolf Zechner and Robert Zimmermann and Rolf Breinbauer",

year = "2020",

month = aug,

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doi = "10.1016/j.bmc.2020.115610",

language = "English",

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AU - Mayer, Nicole

AU - Schweiger, Martina

AU - Fuchs, Elisabeth

AU - Migglautsch, Anna K.

AU - Doler, Carina

AU - Grabner, Gernot F.

AU - Romauch,, Matthias

AU - Melcher, Michaela Christina

AU - Zechner, Rudolf

AU - Zimmermann, Robert

AU - Breinbauer, Rolf

PY - 2020/8/15

Y1 - 2020/8/15

N2 - High serum fatty acid (FA) levels are causally linked to the development of insulin resistance, which eventually progresses to type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) generalized in the term metabolic syndrome. Adipose triglyceride lipase (ATGL) is the initial enzyme in the hydrolysis of intracellular triacylglycerol (TG) stores, liberating fatty acids that are released from adipocytes into the circulation. Hence, ATGL-specific inhibitors have the potential to lower circulating FA concentrations, and counteract the development of insulin resistance and NAFLD. In this article, we report about structure–activity relationship (SAR) studies of small molecule inhibitors of murine ATGL which led to the development of Atglistatin. Atglistatin is a specific inhibitor of murine ATGL, which has proven useful for the validation of ATGL as a potential drug target.

AB - High serum fatty acid (FA) levels are causally linked to the development of insulin resistance, which eventually progresses to type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) generalized in the term metabolic syndrome. Adipose triglyceride lipase (ATGL) is the initial enzyme in the hydrolysis of intracellular triacylglycerol (TG) stores, liberating fatty acids that are released from adipocytes into the circulation. Hence, ATGL-specific inhibitors have the potential to lower circulating FA concentrations, and counteract the development of insulin resistance and NAFLD. In this article, we report about structure–activity relationship (SAR) studies of small molecule inhibitors of murine ATGL which led to the development of Atglistatin. Atglistatin is a specific inhibitor of murine ATGL, which has proven useful for the validation of ATGL as a potential drug target.

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KW - Lipolysis

KW - NAFLD

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Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL)

Abstract

Keywords

ASJC Scopus subject areas

Fields of Expertise

UN SDGs

Access to Document

Other files and links

Fingerprint

Atglistatin - Preclinical development of small molecule inhibitors targeting human adipose triglyceride lipase

FWF-Inhibitoren für hATGL - Development of Small Molecule Inhibitors Targeting Human Adipose Triglyceride Lipase

Cite this

Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL)

Abstract

Keywords

ASJC Scopus subject areas

Fields of Expertise

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Atglistatin - Preclinical development of small molecule inhibitors targeting human adipose triglyceride lipase

FWF-Inhibitoren für hATGL - Development of Small Molecule Inhibitors Targeting Human Adipose Triglyceride Lipase

Cite this