Discovery of a Potent, Selective, and Orally Efficacious Pyrimidinooxazinyl Bicyclooctaneacetic Acid Diacylglycerol Acyltransferase-1 Inhibitor

Birch, Alan M.; Birtles, Susan; Buckett, Linda K.; Kemmitt, Paul D.; Smith, Graham J.; Smith, Tim J.D.; Turnbull, Andrew V.; Wang, Steven J Y

doi:10.1021/jm801507v

Cited by 71 publications

(103 citation statements)

References 18 publications

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“…Pharmacological or dietary factors capable of inhibiting intestinal DGAT1 activity specifically may thus be benefi cial for reducing obesity and hepatic steatosis. In fact, several DGAT1 inhibitors have shown effects on the intestine and dietary fat absorption (40)(41)(42).…”

Section: Downloaded Frommentioning

confidence: 99%

Intestine-specific expression of acyl CoA:diacylglycerol acyltransferase 1 reverses resistance to diet-induced hepatic steatosis and obesity in Dgat1 mice

Lee

Fast

Zhu

et al. 2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org lipids and bile acids present in bile to form micelles. Free fatty acids and monoacylglycerol are then taken up by the absorptive cells of the small intestine, enterocytes, where they are resynthesized into TGs and incorporated into the core of chylomicrons, which are secreted via the lymphatic system into circulation ( 2 ). TG is then delivered to cells throughout the body, where it serves diverse functions, including energy storage and generation depending on energy status. The postprandial triglyceridemic response (or levels of TG in blood after a meal) is thus dependent on both the appearance of TG in and the clearance of TG from circulation. Because of its high energy density, high effi ciency of absorption, ability to be stored when energy is in excess, and ability to be oxidized to generate energy when needed, dietary fat and its absorption by the small intestine are important determinants of energy balance.TGs synthesized within enterocytes are secreted into circulation in a time-and amount-dependent manner. As the amount of dietary fat increases, postprandial triglyceridemia also increases ( 3, 4 ). In addition, under HF dietary challenges, TG is also found packaged in enterocytes in cytoplasmic lipid droplets (CLDs) ( 5 ). We recently demonstrated that this storage pool of TG in enterocytes expands and depletes relative to the fed-fasted state and is present whether mice are acutely or chronically challenged by high levels of dietary fat ( 5 ). These results suggest that TG stored in CLDs are eventually hydrolyzed, reesterifi ed, and secreted on chylomicrons. The absorption of dietary fat, the most energy-dense nutrient, by the small intestine is a highly effi cient process. Greater than 95% of dietary fat consumed is absorbed whether a low-or high-fat (HF) diet is consumed ( 1 ), as evidenced by the small amount of fat that is excreted in feces. In the small intestine lumen, dietary fat in the form of triacylglycerol (TG) is hydrolyzed to generate free fatty acids and monoacylglycerol by pancreatic lipase. These products are then emulsifi ed with the help of phospho-

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Section: Downloaded Frommentioning

confidence: 99%

Intestine-specific expression of acyl CoA:diacylglycerol acyltransferase 1 reverses resistance to diet-induced hepatic steatosis and obesity in Dgat1 mice

Lee

Fast

Zhu

et al. 2010

Journal of Lipid Research

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“…These findings suggest and encourage our exploration of novel DGAT-1 inhibitors, since pharmacological inhibition of DGAT-1 may be a feasible therapeutic strategy for human obesity and type 2 diabetes. Recent studies [7][8][9] have demonstrated that small molecule DGAT-1 inhibitors (I, II) showed the similar antiobesity effects previously demonstrated in DGAT-1 deficient mice. Both of compounds (I, II) have a similar linear structure with a terminal carboxylic acid group.…”

mentioning

confidence: 85%

Novel Acyl Coenzyme A: Diacylglycerol Acyltransferase 1 Inhibitors-Synthesis and Biological Activities of N-(Substituted heteroaryl)-4-(substituted phenyl)-4-oxobutanamides

Nakada

Ogino

Asano

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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In a program to discover new small molecule diacylglycerol acyltransferase (DGAT)-1 inhibitors, screening of our in-house chemical library was carried out using recombinant human DGAT-1 enzyme. From this library, the lead compound 1a was identified as a new class of DGAT-1 inhibitor. A series of novel N-(substituted heteroaryl)-4-(substituted phenyl)-4-oxobutanamides 2 was designed from 1a, synthesized and evaluated for inhibitory activity against DGAT-1 enzyme. Among these compounds, N-(5-benzyl-4-phenyl-1,3-thiazol-2-yl)-4-(4,5-diethoxy-2-methylphenyl)-4-oxobutanamide 9 was found to exhibit potent inhibitory activity and good enzyme selectivities. Following administration in KKA y mice with 3 mg/kg high fat diet admixture for four weeks, 9 reduced body weight gain and white adipose tissue weight without affecting total food intake. These results suggested that the small molecule DGAT-1 inhibitor might have potential in the treatment of obesity and metabolic syndrome.

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“…Subsequent experiments using selective inhibitors of microsomal triglyceride transfer protein (MTP) in mice and DGAT1 in nonhuman primates highlight the utility of this approach to assess perturbations in lipid assembly resulting from pharmacological intervention. Comparability between treated and control groups in labeling of the precursor pool is demonstrated for each experiment, allowing the specifi city was obtained when the fragment ion selected for quantitation preserved the 13 C label (enhanced discrimination against isobaric chemical interferences).…”

Section: Experiments 2 Intravenous Administration Of Isotope: Effect mentioning

confidence: 99%

“…On the morning of study, overnight-fasted animals were treated with vehicle (20% TPGS) or one of two doses of DGAT1 inhibitor (0.3 and 3.0 mg/ kg) ( 13 ), with the solution mixed into a yogurt treat for conscious dosing 1 h prior to tracer administration. …”

Section: Experiments 3 Effect Of a Dgat1 Inhibitor On Distribution Ofmentioning

confidence: 99%

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The use of stable-isotopically labeled oleic acid to interrogate lipid assembly in vivo: assessing pharmacological effects in preclinical species

McLaren

Wang

et al. 2011

Journal of Lipid Research

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This article is available online at http://www.jlr.orgUnderstanding the synthesis and disposition of triglycerides, cholesteryl esters, and phospholipids is an important component in developing effective therapies to treat cardiovascular and metabolic disease. The kinetics of synthesis and disposition can be ascertained by introducing a labeled substrate and measuring its incorporation into and decay from bulk lipid pools, which provides useful information on the fl ux of lipid through the relevant synthetic and metabolizing pathways. Such techniques have been used to study the kinetics of synthesis of VLDL triglycerides ( 1-3 ), cholesterol ( 4, 5 ), and phospholipids ( 6 ), as well as many other aspects of lipid disposition. When introducing a labeled substrate into a biological system, the pattern of labeling in downstream metabolites conveys information about the synthesis of the product. By experimentally measuring this labeling pattern and comparing the results to those predicted by combinatorial probability, it is possible to determine kinetic parameters. This technique has been termed mass isotopomer distribution analysis (MIDA); discussions on consideration for use and limits of applicability of the method have been presented previously ( 7,8 ). A central tenet of MIDA is that differences in the observed concentration of a particular isotopomeric product can be due solely to the relative abundances of the labeled precursor and the endogenous form of the substrate, i.e., the labeling of the precursor pool. In effect, introduction of the label represents an intervention on the system, and this carries important ramifi cations for interpreting observed effects when a second Abstract The use of stable isotopically labeled substrates and analysis by mass spectrometry have provided substantial insight into rates of synthesis, disposition, and utilization of lipids in vivo. The information to be gained from such studies is of particular benefi t to therapeutic research where the underlying causes of disease may be related to the production and utilization of lipids. When studying biology through the use of isotope tracers, care must be exercised in interpreting the data to ensure that any response observed can truly be interpreted as biological and not as an artifact of the experimental design or a dilutional effect on the isotope. We studied the effects of dosing route and tracer concentration on the mass isotopomer distribution profi le as well as the action of selective inhibitors of microsomal triglyceride transfer protein (MTP) in mice and diacylglycerol acyltransferase 1 (DGAT1) in nonhuman primates, using a stable-isotopically labeled approach. Subjects were treated with inhibitor and subsequently given a dose of uniformly 13 C-labeled oleic acid. Samples were analyzed using a rapid LC-MS technique, allowing the effects of the intervention on the assembly and disposition of triglycerides, cholesteryl esters, and phospholipids to be determined in a single 3 min run from just 10 l of plasma. Press, March...

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Discovery of a Potent, Selective, and Orally Efficacious Pyrimidinooxazinyl Bicyclooctaneacetic Acid Diacylglycerol Acyltransferase-1 Inhibitor

Cited by 71 publications

References 18 publications

Intestine-specific expression of acyl CoA:diacylglycerol acyltransferase 1 reverses resistance to diet-induced hepatic steatosis and obesity in Dgat1 mice

Intestine-specific expression of acyl CoA:diacylglycerol acyltransferase 1 reverses resistance to diet-induced hepatic steatosis and obesity in Dgat1 mice

Novel Acyl Coenzyme A: Diacylglycerol Acyltransferase 1 Inhibitors-Synthesis and Biological Activities of N-(Substituted heteroaryl)-4-(substituted phenyl)-4-oxobutanamides

The use of stable-isotopically labeled oleic acid to interrogate lipid assembly in vivo: assessing pharmacological effects in preclinical species

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