Diacylglycerol Acyltransferase Inhibitors Research Articles

Novel acyl coenzyme A (CoA): Diacylglycerol acyltransferase-1 inhibitors: Synthesis and biological activities of diacylethylenediamine derivatives

A series of diacylethylenediamine derivatives were synthesized and evaluated for their inhibitory activity against DGAT-1 and pharmacokinetic profile to discover new small molecule DGAT-1 inhibitors. Among the compounds, N-[2-({[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)ethyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 3x showed potent inhibitory activity and excellent PK profile. Oral administration of 3x to mice with dietary-induced obesity resulted in reduced body weight gain and white adipose tissue weight.

Inhibitors of diacylglycerol acyltransferase: a review of 2008 patents

Background: Postprandial hypertriglyceridemia has been identified as a major independent risk factor for future cardiovascular events. Therefore, inhibition of triglyceride synthesis has enormous therapeutic potential in the treatment of metabolic disorders. Diacylglycerol acyltransferase (DGAT) enzymes catalyze the final and only committed step in triglyceride biosynthesis and have thus been identified as potential therapeutic targets to combat human cardio-metabolic diseases.Objective/method: Significant interest in DGAT-1 inhibitors has emerged in the last several years. To provide a perspective on the exciting features of this enzyme for targeting metabolic diseases, a summary of the biology and pharmacology surrounding the DGAT enzymes is presented. Following this is a discussion of the various chemotypes that have been disclosed within relevant patent applications published in 2008. Specifically, the similarities and differences of the chemical structures and the biological data that are provided to support the corresponding claims are presented.Conclusion: Small molecule and biologic-based DGAT inhibitors have been successfully used for the preclinical validation of DGAT enzymes as targets for the treatment of metabolic diseases. Given the advanced stage in which some of the chemical matter resides, it is expected that DGAT inhibitors will enter the clinic in the coming years.

Diacylglycerol acyltransferase-inhibitory compounds from Erythrina senegalensis

Inhibition of acyl CoA:diacylglycerol acyltransferase (DGAT) is proposed to be a drug target for the treatment of obesity and type 2 diabetes. Bioassay-guided fractionation of the CH(2)Cl(2)-soluble extract of the stem bark of Erythrina senegalensis, using an in vitro DGAT enzyme assay, resulted in the isolation of eight known prenylflavonoids, 8-prenylleutone (1), auriculatin (2), erysenegalensein O (3), erysenegalensein D (4), erysenegalensein N (5), derrone (6), alpinumisoflavone (7), and 6,8-diprenylgenistein (8). Compounds 1, 2-4, 6, and 8 inhibited DGAT activity, with IC(50) values ranging from 1.1 +/- 0.3 to 15.1 +/- 1.1 microg/mL. On the basis of the data obtained, we propose isoflavonoids with isoprenyl groups as a novel class of DGAT inhibitors.

Expression of two human acyl-CoA:diacylglycerol acyltransferase isozymes in yeast and selectivity of microbial inhibitors toward the isozymes

Two isozymes for human acyl-coenzyme A:diacylglycerol acyltransferase (DGAT), DGAT1 and DGAT2, were independently expressed in DGAT-deficient Saccharomyces cerevisiae to establish DGAT1- and DGAT2-S. cerevisiae. The selectivity of DGAT inhibitors of natural origin towards the isozymes was assessed in enzyme assays using the microsomal fractions prepared from DGAT1- and DGAT2-S. cerevisiae. Amidepsines and xanthohumol inhibited DGAT1 and DGAT2 with similar potency, whereas roselipins were found to inhibit DGAT2 selectively.

A simple homogeneous scintillation proximity assay for acyl-coenzyme A:diacylglycerol acyltransferase

Acyl-coenzyme A:diacylglycerol acyltransferase (DGAT) is a key enzyme in triacylglycerol synthesis, and inhibiting this enzyme is a promising approach for treating obesity, type II diabetes, and dyslipidemia. There are two distinct DGAT enzymes: DGAT1 and DGAT2. The conventional assay for measuring DGAT activity is a thin layer chromatography (TLC) method, which is not amenable to screening a large number of compounds. To increase the throughput, we have developed a novel, homogeneous scintillation proximity assay (SPA) for DGAT. In this assay, when 3H-labeled acyl-CoA is used as the acyl donor and diacylglycerol is used as the acyl acceptor, the 3H-labeled triacylglycerol product formed in the reaction binds to polylysine SPA beads, producing a signal that is measured in a TopCount or LEADseeker. The apparent Michaelis–Menten kinetic parameters determined by this DGAT SPA method agreed well with the values determined with the conventional TLC assay. The statistical values also indicate that the DGAT SPA is a robust assay, with a Z′ of more than 0.60 and a signal/background ratio of approximately 9. These results suggest that the current assay provides high-throughput capacity for the identification of DGAT inhibitors.

New Polyacetylenes, DGAT inhibitors from the roots of Panax ginseng.

The petroleum ether extract of Panax ginseng showed a significant inhibition of the diacylglycerol acyltransferase (DGAT) enzyme from rat liver microsomes. Bioactivity-guided fractionation led to the isolation of two new polyacetylenic compounds, (9 R,10 S)-epoxyheptadecan-4,6-diyn-3-one ( 1) and 1-methoxy-(9 R,10 S)-epoxyheptadecan-4,6-diyn-3-one ( 2). Their chemical structures were elucidated on the basis of spectroscopic evidence and asymmetric synthesis. IC50 values of 9 microg/mL ( 1) and 32 microg/mL ( 2) were obtained.

Core structure in roselipins essential for eliciting inhibitory activity against diacylglycerol acyltransferase.

Fungal roselipins, discovered as inhibitors of diacylglycerol acyltransferase (DGAT), consist of three parts; highly methylated C20 fatty acid, mannose and arabinitol. Demannosyl and/or dearabinitoyl roselipins were prepared chemically or enzymatically. Demannnosyl roselipins conserved the DGAT inhibitory activity, but the others lost the activity, indicating that the arabinitoyl fatty acid core is essential for eliciting the activity.

ChemInform Abstract: Structure Elucidation of Roselipins, Inhibitors of Diacylglycerol Acyltransferase, Produced by Gliocladium roseum KF‐1040.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Roselipins, inhibitors of diacylglycerol acyltransferase, produced by Gliocladium roseum KF-1040.

Gliocladium roseum KF-1040, a marine isolate, was found to produce a series of new inhibitors of diacylglycerol acyltransferase (DGAT). Four active compounds, designated roselipins 1A, 1B, 2A and 2B, were isolated from the fermentation broth of the producing strain by solvent extraction, ODS column chromatography and preparative HPLC. The highest production of roselipins was observed when cultured in the medium containing natural sea water. Roselipins inhibit DGAT activity with IC50 values of 15 approximately 22 microM in an enzyme assay system using rat liver microsomes.

Structure elucidation of roselipins, inhibitors of diacylglycerol acyltransferase produced by Gliocladium roseum KF-1040.

The structures of roselipins 1A, 1B, 2A and 2B were elucidated by spectroscopic studies including 1H-1H COSY, 13C-1H COSY, 13C-1H HMQC and 13C-1H HMBC NMR experiments, and degradation experiments. They have the common skeleton of 2,4,6,8,10,12,14,16,18-nonamethyl-5,9,13-trihydroxy-2E,6E, 10E-icosenoic acid modified with a D-mannose and a D-arabinitol. Roselipin A and B groups were stereoisomers at the arabinitol moiety, which esterified the fatty acid from the different terminal hydroxy residue. Roselipin 2 group was 6"-O-acetyl roselipin 1 group.

Xanthohumols, diacylglycerol acyltransferase inhibitors, from Humulus lupulus

Two inhibitors of diacylglycerol acyltransferase (DGAT) were isolated from hops of Humulus lupulus (L.). The structure elucidation and DGAT inhibitory activities were studied.

ChemInform Abstract: Amidepsine E, an Inhibitor of Diacylglycerol Acyltransferase Produced by Humicola sp. FO‐5969.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Amidepsine E, an inhibitor of diacylglycerol acyltransferase produced by Humicola sp. FO-5969.

Amidepsine E, an inhibitor of diacylglycerol acyltransferase produced by Humicola sp. FO-5969.

Amidepsines, inhibitors of diacylglycerol acyltransferase produced by Humicola sp. FO-2942. I. Production, isolation and biological properties.

Humicola sp. FO-2942, a soil isolate, was found to produce a series of new inhibitors of diacylglycerol acyltransferase (DGAT). Three active compounds, designated amidepsines A, B and C, were isolated from the fermentation broth of the producing strain by solvent extraction, silica gel column chromatography, ODS column chromatography and HPLC. Amidepsines inhibit DGAT activity with IC50 values of 10.2 approximately 51.6 microM in an enzyme assay system using rat liver microsomes. Amidepsines also showed specific inhibition of triacylglycerol formation in intact Raji cells, indicating that they inhibit DGAT activity in living cells.

Inhibition of diacylglycerol acyltransferase by 2-bromooctanoate in cultured rat hepatocytes.

Triacylglycerol synthesis in cultured rat hepatocytes was inhibited by 2-bromooctanoate with a concomitant accumulation of diacylglycerols. 2-Bromooctanoate inhibition could be ascribed to its thioesterification by medium chain fatty acyl-CoA synthase (Raaka, B.M., and Lowenstein, J.M. (1979) J. Biol. Chem. 254, 6755-6762) with 2-bromooctanoyl-CoA acting as a competitive inhibitor of diacylglycerol acyltransferase. The Ki of 2-bromooctanoyl-CoA was 1.5 microM compared with a Km of 25 microM for the palmitoyl-CoA substrate. Diacylglycerol esterification was also inhibited by C12-C16 2-bromo fatty acids. However, inhibition of triacylglycerol synthesis by long chain 2-bromo fatty acids was accompanied by decreased overall neutral lipid synthesis as a result of inhibition of the long chain fatty acyl-CoA synthase. Since 2-bromooctanoate was a poor inhibitor of the long chain fatty acyl-CoA synthase, it appears to function selectively as an inhibitor of diacylglycerol acyltransferase in cultured rat hepatocytes.

Drugs affecting the synthesis of glycerides and phospholipids in rat liver. The effects of clofibrate, halofenate, fenfluramine, amphetamine, cinchocaine, chlorpromazine, demethylimipramine, mepyramine and some of their derivatives.

The effects on glycerolipid synthesis of a series of compounds including many drugs were investigated in cell-free preparations and slices of rat liver. p-Chlorobenzoate, p-chlorophenoxyisobutyrate, halofenate, D-amphetamine, adrenaline, procaine and N-[2-(4-chloro-3-sulphamoylbenzoyloxy)ethyl]norfenfluramine had little inhibitory effect on any of the systems investigated. Two amphiphilic anions, clofenapate and 2-(p-chlorophenyl)-2-(m-trifluoromethylphenoxy)acetate, both inhibited glycerol phosphate acyltransferase and diacylglycerol acyltransferase at approx. 1.6 and 0.7 mm respectively. Clofenapate (1 mm) also inhibited the incorporation of glycerol into lipids by rat liver slices without altering the relative proportions of the different lipids synthesized. The amphilic amines, mepyramine, fenfluramine, norfenfluramine, hydroxyethylnorfenfluramine, N-(2-benzoyloxyethyl)norfenfluramine, cinchocaine, chlorpromazine and demethylimipramine inhibited phosphatidate phosphohydrolase by 50% at concentrations between 0.2 and 0.9 mm. The last four compounds inhibited glycerol phosphate acyltransferase by 50% at concentrations between 1 and 2.6 mm. None of the amines examined appeared to be an effective inhibitor of diacylglycerol acyltransferase. Norfenfluramine, hydroxyethylnorfenfluramine and N-(2-benzoyloxyethyl)norfenfluramine produced less inhibition of glycerol incorporation into total lipids than was observed with equimolar clofenapate. The major effect of these amines in liver slices was to inhibit triacylglycerol and phosphatidylcholine synthesis and to produce a marked accumulation of phosphatidate. The results are discussed in terms of the control of glycerolipid synthesis. They partly explain the observed effects of the various drugs on lipid metabolism. The possible use of these compounds as biochemical tools with which to investigate the reactions of glycerolipid synthesis is considered.