In vitro SAR of (5-(2H)-isoxazolonyl) ureas, potent inhibitors of hormone-sensitive lipase

Lowe, Derek; Magnuson, Steven; Qi, Ning; Campbell, Ann-Marie; Cook, Jack; Hong, Zhenqiu; Wang, Ming; Rodriguez, Mareli; Achebe, Furahi; Kluender, Harold C.; Wong, Wai C.; Bullock, William H.; Salhanick, Arthur I.; Witman-Jones, Terri; Bowling, Mary E.; Keiper, Christine; Clairmont, Kevin B.

doi:10.1016/j.bmcl.2004.04.015

Cited by 57 publications

(15 citation statements)

References 27 publications

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“…We confirmed that 1 inhibits the SH FAAH by covalent carbamoylation of the enzyme’s serine nucleophile 16 . There are a handful of other reports of N -heterocyclic ureas (NHUs) as SH inhibitors, including an isoxazolonyl urea 17 (middle, Fig. 1a) and a 1,2,4-triazole urea 18 (bottom, Fig.…”

Section: Resultsmentioning

confidence: 99%

Click-generated triazole ureas as ultrapotent in vivo–active serine hydrolase inhibitors

et al. 2011

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Serine hydrolases (SHs) are a diverse enzyme class representing > 1% of all human proteins. The biological functions for most SHs remain poorly characterized due to a lack of selective inhibitors to probe their activity in living systems. Here, we show that a substantial number of SHs can be irreversibly inactivated by 1,2,3-triazole ureas, which exhibit negligible cross-reactivity with other protein classes. Rapid lead optimization by click chemistry-enabled synthesis and competitive activity-based profiling identified 1,2,3-triazole ureas that selectively inhibit enzymes from diverse branches of the SH superfamily, including peptidases (acyl-peptide hydrolase or APEH), lipases (platelet-activating factor acetylhyrolase-2 or PAFAH2), and uncharacterized hydrolases (α, β-hydrolase 11 or ABHD11), with exceptional potency in cells (sub-nM) and mice (< 1 mg/kg). We show that APEH inhibition leads to accumulation of N-acetylated proteins and promotes proliferation in T-cells. These data designate 1,2,3-triazole ureas as a pharmacologically privileged chemotype for SH inhibition that shows broad activity across the SH class coupled with tunable selectivity for individual enzymes.

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Section: Resultsmentioning

confidence: 99%

Click-generated triazole ureas as ultrapotent in vivo–active serine hydrolase inhibitors

et al. 2011

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“…Close analogs of these carboxamides have been cited in the literature as effective serine hydrolase inhibitors. Isoxazolonyl carboxamide 22 28 and 1,2,4-triazole carboxamide 23 29 are potent hormone-sensitive lipase (HSL) inhibitors (Figure 5). Like vertebrate AChE, HSL belongs to the family of serine hydrolases with a α/β hydrolase fold.…”

Section: Discussionmentioning

confidence: 99%

3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae

Verma

Wong

Islam

et al. 2015

Bioorganic & Medicinal Chemistry

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To identify potential selective and resistance-breaking mosquitocides against the African malaria vector Anopheles gambiae, we investigated the acetylcholinesterase (AChE) inhibitory and mosquitocidal properties of isoxazol-3-yl dimethylcarbamates (15), and the corresponding 3-oxoisoxazole-2(3H)-dimethylcarboxamide isomers (14). In both series, compounds were found with excellent contact toxicity to wild-type susceptible (G3) strain and multiply resistant (Akron) strain mosquitoes that carry the G119S resistance mutation of AChE. Compounds possessing good to excellent toxicity to Akron strain mosquitoes inhibit the G119S mutant of An. gambiae AChE (AgAChE) with ki values at least 10- to 600-fold higher than that of propoxur, a compound that does not kill Akron mosquitoes at the highest concentration tested. On average, inactivation of WT AgAChE by dimethylcarboxamides 14 was 10-20 fold faster than that of the corresponding isoxazol-3-yl dimethylcarbamates 15. X-ray crystallography of dimethylcarboxamide 14d provided insight into that reactivity, a finding that may explain the inhibitory power of structurally-related inhibitors of hormone-sensitive lipase. Finally, human/An. gambiae AChE inhibition selectivities of these compounds were low, suggesting the need for additional structural modification.

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“…The experiments were carried out between days 12 and 15. Pharmacological treatment of cells was performed during functional measurements (3 h) with the adenylate cyclase activator forskolin (FK) and/or specific HSL inhibitor Bay (22,27). Primary culture of differentiated preadipocytes was performed as previously described (28).…”

Section: Methodsmentioning

confidence: 99%

Contribution of Adipose Triglyceride Lipase and Hormone-sensitive Lipase to Lipolysis in hMADS Adipocytes

Bézaire

Mairal

Ribet

et al. 2009

Journal of Biological Chemistry

196

150

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Lipolysis is the catabolic pathway by which triglycerides are hydrolyzed into fatty acids. Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) have the capacity to hydrolyze in vitro the first ester bond of triglycerides, but their respective contributions to whole cell lipolysis in human adipocytes is unclear. Here, we have investigated the roles of HSL, ATGL, and its coactivator CGI-58 in basal and forskolin-stimulated lipolysis in a human white adipocyte model, the hMADS cells. The hMADS adipocytes express the various components of fatty acid metabolism and show lipolytic capacity similar to primary cultured adipocytes. We show that lipolysis and fatty acid esterification are tightly coupled except in conditions of stimulated lipolysis. Immunocytochemistry experiments revealed that acute forskolin treatment promotes HSL translocation from the cytosol to small lipid droplets and redistribution of ATGL from the cytosol and large lipid droplets to small lipid droplets, resulting in enriched colocalization of the two lipases. HSL or ATGL overexpression resulted in increased triglyceride-specific hydrolase capacity, but only ATGL overexpression increased whole cell lipolysis. HSL silencing had no effect on basal lipolysis and only partially reduced forskolin-stimulated lipolysis. Conversely, silencing of ATGL or CGI-58 significantly reduced basal lipolysis and essentially abolished forskolin-stimulated lipolysis. Altogether, these results suggest that ATGL/CGI-58 acts independently of HSL and precedes its action in the sequential hydrolysis of triglycerides in human hMADS adipocytes.Adipose tissue fat stores in humans are mainly dependent upon fatty acid (FA) 2 supply, FA esterification to triglycerides (TG), and TG breakdown, or lipolysis. Adipose tissue lipolysis is governed by three lipases. Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) both have the capacity to initiate TG degradation by cleaving the first ester bond, but HSL is unique in its capacity to break down the second ester bond, converting diglycerides (DG) to monoglycerides (1-3). The non-rate-limiting monoglyceride lipase completes lipolysis by cleaving the last ester bond from a monoglyceride molecule, leading to glycerol release (4). Adipose tissue lipolysis has received much attention over the past 10 years because of its altered regulation in obesity (5).HSL resides freely in the cytosol and can associate with lipid droplets (LD). It is regulated by hormones such as catecholamines, insulin, and natriuretic peptides. Catecholamines bind to ␤-adrenoceptors on adipocyte cell membranes and activate cyclic AMP-dependent protein kinase. Similarly, natriuretic peptides bind to type A receptors and activate cyclic GMPdependent protein kinase (6). The protein kinase action in stimulated lipolysis is 2-fold: 1) phosphorylation of HSL, leading to its translocation from the cytosol to LD (7,8), and 2) phosphorylation of perilipin A (6, 9, 10), the predominant perilipin isoform in adipocytes, enhancing interaction be...

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In vitro SAR of (5-(2H)-isoxazolonyl) ureas, potent inhibitors of hormone-sensitive lipase

Cited by 57 publications

References 27 publications

Click-generated triazole ureas as ultrapotent in vivo–active serine hydrolase inhibitors

Click-generated triazole ureas as ultrapotent in vivo–active serine hydrolase inhibitors

3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae

Contribution of Adipose Triglyceride Lipase and Hormone-sensitive Lipase to Lipolysis in hMADS Adipocytes

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