Synthesis and Structure−Activity Relationship for a Novel Class of Potent and Selective Carbamate-Based Inhibitors of Hormone Selective Lipase with Acute In Vivo Antilipolytic Effects

Ebdrup, Søren; Refsgaard, Hanne H. F.; Fledelius, Christian; Jacobsen, Poul

doi:10.1021/jm0607653

Cited by 34 publications

(26 citation statements)

References 38 publications

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“…ThioGlo-1 was from Covalent Associates (Corvallis, OR). ATGL inhibitors ATGListatin ( 17 ) and WWL64, HSL inhibitors WWL11 ( 18 ) and Compound 13f ( 19 ), DAGL inhibitors KT109 and KT172, and ABHD6 inhibitor KT195 ( 20 ) were synthesized according to the published procedures. All stock solutions of inhibitors were prepared in dimethylsulfoxide and diluted in assay medium at required concentrations just prior to assays.…”

Section: Methodsmentioning

confidence: 99%

“…An HSL inhibitor, WWL11, discovered using the activitybased protein profi ling approach against mouse HSL ( 18 ), was found to have much less effect on hHSL but significantly inhibited hCES1. Another mouse HSL-directed inhibitor, Compound 13f, described recently ( 19 ), also showed much less inhibition of hHSL, but it inhibited both hABHD6 and hCES1 ( Table 1 ). DAGL ␣ inhibitors.…”

Section: Abhd6 Activity and Inhibitionmentioning

confidence: 97%

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Simplified assays of lipolysis enzymes for drug discovery and specificity assessment of known inhibitors

Iglesias

Lamontagne

Erb

et al. 2016

Journal of Lipid Research

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is also an important source of several metabolic signals. As an integral part of the glycerolipid/fatty acid cycle ( 1 ), lipolysis produces lipid signals that modify cellular functions such as glucose-stimulated insulin secretion ( 2 ) and metabolic pathways and also alter transcription of various genes ( 1, 3 ). TG breakdown to glycerol and fatty acids is accomplished by the sequential action of adipose triglyceride lipase (ATGL), which hydrolyzes TG to 2,3-or 1,3-diacylglycerol (DAG), followed by hormone sensitive lipase (HSL)-mediated DAG hydrolysis to generate 1-or 2-monoacylglycerol (MAG) ( 1, 3 ). Finally MAG is hydrolyzed by either the classical MAG lipase (MAGL) or the recently described ␣ / ␤ -hydrolase domain 6 (ABHD6) to glycerol and FFA ( 4-6 ). Receptor-mediated signaling at the plasma membrane leads to the phospholipase-C-dependent formation of 1,2-DAG, which is further hydrolyzed by sn -1-DAG lipases (DAGL) ␣ or ␤ ( 7 ), to form mostly 2-MAG.Recent studies indicated the physiological importance of many of these lipases. Thus, ATGL has been implicated in lipid homeostasis in adipocytes, myocardium and skeletal muscle, cancer cachexia ( 1,3,8 ), and the regulation of insulin secretion in pancreatic ␤ -cells ( 9 ). HSL was shown to be important in adipose lipid metabolism ( 10 ) and in the regulation of glucose-stimulated insulin secretion ( 11,12 ). MAGL, which hydrolyzes the endocannabinoid Abstract Lipids are used as cellular building blocks and condensed energy stores and also act as signaling molecules. The glycerolipid/ fatty acid cycle, encompassing lipolysis and lipogenesis, generates many lipid signals. Reliable procedures are not available for measuring activities of several lipolytic enzymes for the purposes of drug screening, and this resulted in questionable selectivity of various known lipase inhibitors. We now describe simple assays for lipolytic enzymes, including adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), sn -1-diacylglycerol lipase (DAGL), monoacylglycerol lipase, ␣ / ␤ -hydrolase domain 6, and carboxylesterase 1 (CES1) using recombinant human and mouse enzymes either in cell extracts or using purifi ed enzymes. We observed that many of the reported inhibitors lack specifi city. Thus, Cay10499 (HSL inhibitor) and RHC20867 (DAGL inhibitor) also inhibit other lipases. Marked differences in the inhibitor sensitivities of human ATGL and HSL compared with the corresponding mouse enzymes was noticed. Thus, ATGListatin inhibited mouse ATGL but not human ATGL, and the HSL inhibitors WWL11 and Compound 13f were effective against mouse enzyme but much less potent against human enzyme. Many of these lipase inhibitors also inhibited human CES1. Results describe reliable assays for measuring lipase activities that are amenable for drug screening and also caution about the specifi city of the many earlier described lipase inhibitors.

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Section: Methodsmentioning

confidence: 99%

Section: Abhd6 Activity and Inhibitionmentioning

confidence: 97%

Simplified assays of lipolysis enzymes for drug discovery and specificity assessment of known inhibitors

Iglesias

Lamontagne

Erb

et al. 2016

Journal of Lipid Research

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“…BAY 59-9435 (BAY, dissolved in 0.5% methylcellulose), a highly selective HSL inhibitor (28 -30), was chemically synthesized, as described (30). Novo 13f, another highly selective HSL inhibitor (31), was a generous gift of Dr. Christian Fledelius (Novo Nordisk A/S). Sphk1 antibodies were from Antibody Verify, Inc. (AAS67634C) or Cell Signaling Technology (no.…”

Section: Methodsmentioning

confidence: 99%

“…2A). To confirm the specific involvement of HSL in isoproterenol-induced SphK1 up-regulation, 3T3-L1 cells were pretreated with Novo 13f, another selective HSL inhibitor (31). As shown in Fig.…”

Section: Adrb3/hsl Signaling Induces Sphk1 Expression In Adi-mentioning

confidence: 99%

Adipocyte Lipolysis-stimulated Interleukin-6 Production Requires Sphingosine Kinase 1 Activity

Zhang

Mottillo

Zhao

et al. 2014

Journal of Biological Chemistry

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Background: Lipolysis contributes to adipose inflammation. Results: Lipolysis up-regulates sphingosine kinase 1 (SphK1) in adipocytes. Modulation of SphK1 regulates adipose lipolysisstimulated interleukin 6 production. Conclusion: SphK1 plays a pivotal role in adipose inflammation. Significance: Identification of a role for SphK1 in lipolysis-triggered adipose inflammation. Targeting SphK1 provides a novel intervention for adipose inflammation and associated metabolic syndromes.

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“…105 With a view to limiting deleterious FA release characterizing the metabolic syndrome, several pharmaceutical groups have started to develop small-molecule modulators of lipolysis including HSL inhibitors. 106,107 MGL and TGH inhibitors are also available for in vitro purposes. [108][109][110] As an alternative to transgenic models one could consider in vivo pharmacological chronic treatments with such molecules.…”

mentioning

confidence: 99%

Adipocyte lipases and lipid droplet-associated proteins: insight from transgenic mouse models

Girousse

Langin

2011

Int J Obes

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Adipose tissue lipolysis is the catabolic process whereby stored triacylglycerol (TAG) is broken down by lipases into fatty acids and glycerol. Here, we review recent insights from transgenic mouse models. Genetic manipulations affecting lipases are considered first, followed by transgenic models of lipase co-factors and lastly non-lipase lipid droplet (LD)-associated proteins. The central role of hormone-sensitive lipase (HSL), long considered to be the sole rate-limiting enzyme of TAG hydrolysis, has been revised since the discovery of adipose triglyceride lipase (ATGL). It is now accepted that ATGL initiates TAG breakdown producing diacylglycerol, which is subsequently hydrolyzed by HSL. Furthermore, lipase activities are modulated by co-factors whose deletion causes severe metabolic disturbances. Another major advance has come from the description of the involvement of non-lipase proteins in the regulation of lipolysis. The role of perilipins has been extensively investigated. Other newly discovered LD-associated proteins have also been shown to regulate lipolysis.

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Synthesis and Structure−Activity Relationship for a Novel Class of Potent and Selective Carbamate-Based Inhibitors of Hormone Selective Lipase with Acute In Vivo Antilipolytic Effects

Cited by 34 publications

References 38 publications

Simplified assays of lipolysis enzymes for drug discovery and specificity assessment of known inhibitors

Simplified assays of lipolysis enzymes for drug discovery and specificity assessment of known inhibitors

Adipocyte Lipolysis-stimulated Interleukin-6 Production Requires Sphingosine Kinase 1 Activity

Adipocyte lipases and lipid droplet-associated proteins: insight from transgenic mouse models

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