Modeling the mechanism of action of a dgat1 inhibitor using a. In this study we assessed the safety, tolerability and tglowering efficacy of the dgat1 inhibitor pradigastat in patients with fcs. This is a novel, potent and highly selective, oral diacylglycerolacyltransferase 1 dgat1 inhibitor. Using drosophila and human cells, we show here that seipin, an er protein implicated in ld biology, mediates a discrete step in ld formationthe conversion of small, nascent lds to larger, mature lds. Pdf a practical synthesis of a potent and selective diacylglycerol. In these reports, although pradigastat reduced plasma tg concentrations, it also resulted in a high frequency of gastrointestinal adverse events, including diarrhea and nausea 40. Discovery of a potent and selective dgat1 inhibitor with a.
The ic 50 value for dgat1 inhibition by t863 was similar in the cpm fluorescent assay 49 n m and the tlc assay 17 n m fig. Depletion of the noncentrosomal mtoc protein gm reduced pca cell proliferation and migration. Diacylglyceride acyltransferase 1 dgat1 is the enzyme that adds the final fatty acid on to a diacylglyceride during triglyceride tg synthesis. Early clinical investigation explored its potential for the treatment of hypertriglyceridemia and nafld. Seipin is required for converting nascent to mature lipid.
Diglyceride acyltransferase or oacyltransferase, dgat, catalyzes the formation of triglycerides from diacylglycerol and acylcoa. Dec 02, 2011 here we characterize a tool dgat1 inhibitor compound, t863. We discovered a class of dgat1 inhibitors, which is active in fly and mammalian cell lines as well as whole flies. Aug 26, 2016 how proteins control the biogenesis of cellular lipid droplets lds is poorly understood. Dec 02, 2011 we found that t863 is a potent inhibitor for both human and mouse dgat1 in vitro, which acts on the acylcoa binding site of dgat1 and inhibits dgat1 mediated triacylglycerol formation in cells. Design and optimization of pyrazinecarboxamidebased. A new series of pyrazinecarboxamide dgat1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and dmpk properties combined with a low predicted dose in man. Also, disclosed are methods of using the compound in the treatment of obesity, dyslipidemia, diabetes and atherosclerosis, and to pharmaceutical compositions comprising at least one compound of formula i or a stereoisomer or pharmaceutically acceptable salt thereof.
A novel series of thieno3,2dpyrimidine derivatives were. In an acute lipid challenge model, oral administration of t863 significantly delayed fat. Abstractinhibition of diacylglycerol oacyltransferase 1 dgat1 has been a mechanism of interest for metabolic. P7435 has been developed by the nce research division of pel for the management of metabolic disorders such as lipid abnormalities and diabetes. Our dgat 1 team developed a benzimidazole lead series as exemplified by 1 and 2 in fig. Diacylglycerol acyltransferase1 dgat1 inhibition perturbs. A class of diacylglycerol acyltransferase 1 inhibitors identified by a combination of phenotypic highthroughput. A class of diacylglycerol acyltransferase 1 inhibitors identified by a combination of phenotypic highthroughput screening, genomics, and genetics. In addition, the effects of chronic dgat1 inhibition on glucose and. Either dgat1 or dgat2 inhibitor alone did not attain this effect.
Dgat1 inhibitors the biocompare inhibitor search lets researchers browse thousands of compounds by searching not only by inhibitor name, but also by its target enzyme. In an acute lipid challenge model, oral administration of t863 significantly delayed fat absorption and resulted in lipid accumulation in the distal. The present invention further relates to methods of treating or preventing obesity, and obesityrelated disorders, in a subject in need thereof by administering a composition. Pdf familial chylomicronemia syndrome fcs is a rare lipid disease caused by complete lipoprotein lipase. Chlorella, a unicellular eukaryotic green alga, has attracted much attention as a potential feedstock for renewable energy production. Pf04620110 also possesses greater than 100fold selectivity against hdgat2, hacat1, hawat12, hmgat23, mmgat1. Dgat1 plays a key role in the repackaging of dietary tg into circulating tg rich chylomicrons. Dgat1 inhibitor suppresses prostate tumor growth and migration by regulating intracellular lipids and noncentrosomal mtoc protein gm. Us 20040122033 a1 combination therapy for the treatment of. This gene encodes one of two enzymes which catalyzes the final reaction in the synthesis of triglycerides in which diacylglycerol is covalently bound to long chain fatty acylcoas. Therefore, selective dgat1 inhibitors have been developed to. Oil in the form of triacylglycerols tags is quantitatively the most important storage form of energy for eukaryotic cells.
Both t863 a diacylglycerol oacyltransferase 1 dgat1 inhibitor and 5aminoimidazole4. A class of diacylglycerol acyltransferase 1 inhibitors identified by a. Quantification of lipid storage amounts in fly cells and the activity of ct1 thi4, ct2 tpe5 and ct3 au6 in drosophila kc167 cells. Food was removed from each cage 24 hours prior to administration of dgat1 inhibitor. Identification and characterization of sebaceous gland atrophysparing dgat1 inhibitors plos one, dec 2019 eric s.
Here we show that partial dgat1 deficiency in mice. Diacylglycerol oacyltransferase 2 is a protein that in humans is encoded by the dgat2 gene function. In addition, a known dgat1 inhibitor, lcd344, was examined for inhibition of hdgat1 activity, and ic 50 values were obtained from an 11point dilution series, ranging from 3. Download acrobat pdf file 595kb supplementary data 1. Download the clinical pharmacology in drug development app from the apple.
A growing amount of research has indicated that an exaggerated postprandial circulating tg level is a risk indicator for cardiovascular and metabolic. Rational design and optimization of this series led to the discovery of compound 30 azd7687, which met the project objectives for potency, selectivity, in particular over acat1. The representative compounds 1 and 2 displayed strong potency against human and mouse dgat1 isoforms, but with poor selectivity against acat1 acat1 ic 50 325 nm for 1 and 485 nm for 2 which could cause adrenocortical toxicities. Dgat1 is a triglyceride biosynthetic enzyme with a possible role in metabolic disorders. Effect of the dgat1 inhibitor pradigastat on triglyceride and apob48 levels in patients with familial chylomicronemia syndrome, lipids in health and disease, 2015, pp. We show that deficiencyinhibition of dgat1 affects cholesterol metabolism via reduced chylomicron size and increased transintestinal cholesterol excretion. We have painstakingly mapped out these targets for your convenience, so that you may quickly and painlessly find and decide the right inhibitor for your work. Lipids in health and disease effect of the dgat1 inhibitor pradigastat on triglyceride and apob48 levels in patients with familial chylomicronemia syndrome charles daniel meyers 0 karine tremblay 2 ahmed amer 1 jin chen 1 liewen jiang 0 daniel gaudet 2 0 novartis institutes for biomedical research, cambridge, ma, usa 1 novartis institutes for biomedical research, east hanover. We show that deficiencyinhibition of dgat1 affects cholesterol metabolism via reduced chylomicron size and.
T863 is a potent and specific dgat1 inhibitor that was originally disclosed in a patent application example 2 in the patent. A class of diacylglycerol acyltransferase 1 inhibitors. Identification and characterization of sebaceous gland. Pdf dgat1 inhibitor suppresses prostate tumor growth and. Collectively, we clearly demonstrated that h2003 and 005 are a novel class of dgat2selective inhibitors. To further validate the assay for its hitfinding capability and data reproducibility in screening, assay plates with randomly. The effects of exposure to a 50 hz electric field ef on plasma level of triacylglycerol, free fatty acids, total cholesterol and phospholipid and mrna expression level of diacylglycerol acyltransferase dgat 1 and 2 in liver and intestines from c57bl6 j mice were studied. Pdf on jan 10, 2017, sanjay kumar and others published a novel acylcoa. Targeting diacylglycerol acyltransferase 2 for the treatment.
Dgat1 inhibitor suppresses prostate tumor growth and migration. Familial chylomicronemia syndrome fcs is a rare lipid disease caused by complete lipoprotein lipase lpl deficiency resulting in fasting chylomicronemia and severe hypertriglyceridemia. The reaction catalyzed by dgat is considered the terminal and only committed step in triglyceride synthesis and to be essential for intestinal absorption i. These findings together with the activity of ct2 in cellular systems relevant to human. Effects of a dgat1 inhibitor and a peroxynitrite decomposition catalyst on human. When compared to the control, the treatment with a dgat1 inhibitor significantly reduced the levels of. Diacylglycerol acyltransferase dgat, of which there are two isoforms dgat1 and dgat2, catalyzes the final step in triglyceride synthesis. Discovery of a novel class of diacylglycerol acyltransferase. It has previously been shown that pretreatment of differentiated human skeletal muscle cells myotubes with eicosapentaenoic acid epa promoted increased uptake of fatty acids and increased triacylglycerol accumulation, compared to pretreatment with oleic acid oa and palmitic acid pa. These results suggest a922500 may have beneficial effects in reducing the risk of cardiovascular disease. Accelerating the discovery of dgat1 inhibitors through the application of parallel medicinal chemistry. Suppression of diacylglycerol acyltransferase2 dgat2, but.
Consequences of idgat1 deficiency phenocopy findings in wholebody dgat1. Structural insights into the inhibition mechanism of human. Diacylglycerol oacyltransferase 1 dgat1 has recently become a highly interesting target for metabolic disorders as well as for hepatitis c virus hcv. Dgat1 inhibitors as antiobesity and antidiabetic agents. We evaluated the metabolic impact of pharmacological reduction of dgat1 and 2 expression in liver and fat using antisense oligonucleotides asos in rats with dietinduced nafld. T863, a potent dgat1 inhibitor acting on the acylcoa binding site of dgat1, decreased body weight, improved insulin sensitivity, and alleviated hepatic steatosis in dietinduced obese mice. Treatment of human skeletal muscle cells with inhibitors of. Diacylglycerol acyltransferases dgat 1 and 2 catalyse the final step in triacylglycerol tag synthesis, the esterification of fatty acylcoa to. Additional studies performed address the molecular mechanism by with pharmacological inhibition of dgat1 results in increased gut peptide secretion. Inhibition of diacylglycerol acyltransferase 1 dgat1, which mediates chylomicron triglyceride tg synthesis, is an attractive strategy to reduce tg levels in fcs. We found that t863 is a potent inhibitor for both human and mouse dgat1 in vitro, which acts on the acylcoa binding site of dgat1 and inhibits dgat1 mediated triacylglycerol formation in cells. Us8324241b2 triazolo compounds useful as dgat1 inhibitors. A neuropsychological test to asses attention and response inhibition.
Oct 10, 2019 pdf download pdf of article text and main figures. The present invention relates to compositions comprising an appetite suppressant andor a metabolic rate enhancer andor a nutrient absorption inhibitor useful for the treatment of obesity, and obesityrelated disorders. Effect of the dgat1 inhibitor pradigastat on triglyceride and. Increased triacylglycerol fatty acid substrate cycling in. Inhibition of diacylglycerol acyltransferase 1 dgat1, which mediates chylomicron triglyceride tg. Pharmaceutical companies have developed many novel inhibitors of dgat1, several of which have reached the clinic. Assay development and screening of human dgat1 inhibitors. Nov 27, 2019 the dgat1 inhibitor pradigastat is the most widely studied.
Apexbio dgat1 inhibitordiacylglycerol acyltransferase. The diacylglycerol acyltransferase dgat 1 inhibitor a922500 was shown to effectively reduce postprandial serum triglyceride levels in rodents at concentrations of 0. Effect of the dgat1 inhibitor pradigastat on triglyceride. A representative of this series, 1a, is a potent dgat1 inhibitor with excellent selectivity against acat1 figure. The test was based on comparison between mice post treated with 50 hz ef of 45 kvm intensity for 30 min per day for 11. We report the discovery of a novel series of dgat1 inhibitors in the. Dgat2 the protein is homologous to other membranebound o. May 18, 2020 the soat1 sequences tf105767 were download from treefam 62, aligned by clustal omega and uploaded into the consuf server 63 together with the ci976 pdb files. Effect of the dgat1 inhibitor pradigastat on triglyceride and apob48 levels in patients with familial chylomicronemia syndrome. Accelerating the discovery of dgat1 inhibitors through the. Disclosed are triazolopyridine compounds of formula i, including pharmaceutically acceptable salts thereof. Dgat1 processes diacylglycerol to triglycerides in the final step of resynthesis for the absorption of fat across the intestine. We demonstrate a synergistic effect on the incretin response with the combination of a dgat1 inhibitor and sitagliptin, a dipeptidyl peptidase.
Pdf effect of the dgat1 inhibitor pradigastat on triglyceride and. The representative compounds 1 and 2 displayed strong potency against human and mouse dgat1 isoforms, but with poor selectivity against acat1 acat1 ic 50 325 nm for 1. In this report, we describe in detail the assay development and screening with a lcmsbased system for inhibitors of human diacylglycerol acyltransferase dgat1 with a chemical library of approximately 800,000 compounds. Identification of a botanical inhibitor of intestinal. Finally, combined treatment of h2003 or 005 with a dgat1 inhibitor effectively suppressed oleateinduced ld formation in 3t3l1 preadipose cells. Dgat1 mutation is linked to a congenital diarrheal disorder. Dgat1 inhibitor reduces cell proliferation and migration in. Pdf a practical synthesis of a potent, selective, and orally efficacious diacylglycerol acyltransferase1 dgat1 inhibitor, is described. Most of the disclosed dgat1 inhibitors contained a phenylcyclohexane acetic acid moiety that is apparently critical for dgat1 potency. Pf04620110 is a highly potent and selective inhibitor of dgat1 with an ic50 of 19 nm at human dgat1 and ic50 of 64 nm at rat dgat1. Diacylglycerol acyltransferase dgat is considered the ratelimiting enzyme for tag accumulation. However, the degree of dgat1 inhibition required for metabolic benefits is unclear. The aim of the present study was to examine whether epa could affect substrate cycling in human skeletal.
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