Finally, combined treatment of h2003 or 005 with a dgat1 inhibitor effectively suppressed oleateinduced ld formation in 3t3l1 preadipose cells. However, administration of dgat1 inhibitors in humans resulted in doserelated gastrointestinal side effects, most notably diarrhea 17. Ten milligram per milliliter a92250 dgat1 inhibitor and pf. Aim inhibition of diacylglycerol acyltransferase 1 dgat1 is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. Human pharmacokinetics and safety study of gsk3008356, a selective dgat1 inhibitor, in healthy volunteers. 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. Collectively, we clearly demonstrated that h2003 and 005 are a novel class of dgat2selective inhibitors. By charles daniel meyers, karine tremblay, ahmed amer, jin chen. 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.
Modeling the mechanism of action of a dgat1 inhibitor. Our previous data confirmed that t863 is a potent inhibitor of recombinant human dgat1. P7435 has been developed by the nce research division of pel for the management of metabolic disorders such as lipid abnormalities and diabetes. A hepatitis c ns5a inhibitor used to treat hepatitis c. Oral, selective atpcompetitive inhibitor of p70 s6 kinase s6k1 125. Genetic lossoffunction variants lofs associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We report the design and synthesis of a series of novel dgat1 inhibitors in the benzimidazole class with a pyridyloxycyclohexanecarboxylic acid moiety. Identification, sequence and phylogenetic analysis of cedgat1 in c. Jul 25, 2019 genetic lossoffunction variants lofs associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. Effect of the dgat1 inhibitor pradigastat on triglyceride and apob48 levels in patients with familial chylomicronemia syndrome. Dgat1 plays a key role in the repackaging of dietary tg into circulating tg rich chylomicrons.
Pradigastat, a highly potent and specific diacylglycerol acyltransferase 1 dgat1 inhibitor that blocks chylomicron triglyceride tg synthesis, is an attractive therapy for patients with fcs. Dgat1 is a triglyceride biosynthetic enzyme with a possible role in metabolic disorders. Food was removed from each cage 24 hours prior to administration of dgat1 inhibitor. These data provide insight into the role of dgat1 in the intestinal hormone release and its potential as a drug target for the treatment of type 2 diabetes. In particular, compound 11a is a potent dgat1 inhibitor with excellent selectivity against acat1. Validation of ugt1a1, 1a4, 1a6, 1a9 and 2b7 inhibition. This is a novel, potent and highly selective, oral diacylglycerolacyltransferase 1 dgat1 inhibitor. Ct2 shows in vivo activity and is an inhibitor of dgat1 activity.
Meyers cd, tremblay k, amer a, chen j, jiang l, gaudet d. Thus, inhibition of dgat1 may represent an attractive target for the treatment of obesity or type ii diabetes. Suppression of diacylglycerol acyltransferase2 dgat2, but. Results from a firsttimeinhuman singledose study inhibition of diacylglycerol. A population analysis of the dgat1 inhibitor gsk3008356 and its. Suppression of diacylglycerol acyltransferase2 dgat2. 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. Targeting diacylglycerol acyltransferase 2 for the. The representative compounds 1 and 2 displayed strong potency against human and mouse dgat1 isoforms, but with poor selectivity against acat1. Request pdf proof of mechanism for the dgat1 inhibitor azd7687.
Either dgat1 or dgat2 inhibitor alone did not attain this effect. These results suggest a922500 may have beneficial effects in reducing the risk of cardiovascular disease. The incubation medium was then aspirated and cellular lipids were extracted using butanol containing 0. Effect of the dgat1 inhibitor pradigastat on triglyceride and.
Lcq908 is a new generation of diacylglycerol acyltransferase 1 dgat1 inhibitor as antiobesity and antidiabetic agents. The nucleotide sequence has a full cds of 2,142 bp, encoding a polypeptide of 7 amino acid residues with a. 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. Enzymes in a compartment of the cell called the endoplasmic reticulum catalyze the chemical reactions needed to make these triglycerides. Potent dgat1 inhibitors in the benzimidazole class with a. Seipin is required for converting nascent to mature lipid. Dgat1 inhibitors have potential for the treatment of obesity and a number of dgat 1 inhibitors are in clinical trials for this indication. A growing amount of research has indicated that an exaggerated postprandial circulating tg level is a risk indicator for. Dgat1 inhibitor suppresses prostate tumor growth and migration by regulating intracellular lipids and noncentrosomal mtoc protein gm article pdf available in scientific reports 91.
Apr 01, 2014 aim inhibition of diacylglycerol acyltransferase 1 dgat1 is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. Discovery of an orally bioavailable benzimidazole diacylglycerol acyltransferase 1 dgat1 inhibitor that suppresses body weight gain in dietinduced obese dogs and postprandial triglycerides in humans katsumasa nakajima, ricardo chatelain, kevin b. 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 1 inhibition with azd7687. Dec 02, 2011 t863 is a selective, cellpermeable dgat1 inhibitor that inhibits dgat activity in mouse tissues in vitro. Molecular biology and biotechnology molecular and cell biochemistry series.
Nonalcoholic fatty liver diseases can progress to liver failure but currently lack approved treatments. Dgat1 inhibitor suppresses prostate tumor growth and migration by regulating intracellular lipids and noncentrosomal mtoc protein gm article pdf available in. 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. Diacylglycerol acyltransferase dgat, of which there are two isoforms dgat1 and dgat2, catalyzes the final step in triglyceride synthesis. Diacylglycerol acyltransferase dgat is considered the ratelimiting enzyme for tag accumulation. Dgat1 processes diacylglycerol to triglycerides in the final step of resynthesis for the absorption of fat across the intestine. Indeed, dgat1 inhibitors had significant pharmacologic effects, including decreased tag, which were consistent with the dgat1 knockout mice. Assay development and screening of human dgat1 inhibitors. Acatselective and nonselective dgat1 inhibition sage journals. The diacylglycerol acyltransferase dgat 1 inhibitor a922500 was shown to effectively reduce postprandial serum triglyceride levels in rodents at concentrations of 0. Pdf dgat1 inhibitor suppresses prostate tumor growth and. The cell then stores the triglycerides in a different structure called the lipid droplet. Gsk3008356 is under development as a selective inhibitor of diacylglycerol acyltransferase 1 dgat1, a key enzyme involved in the formation of.
We report the discovery of a novel series of dgat1 inhibitors in the benzimidazole class with a. Pdf diacylglycerol acyltransferase1 dgat1 inhibition. Dgat1 knockout mice are noted to be lean, resistant to obesity and hypertriglyceridemia, making dgat1 inhibition an attractive pharmacologic target for treatment of obesity. Dgat1 deficient murine primary hepatocytes are indeed protected from steatosis by decreased lipogenesis and increased betaoxidation rates villanueva et al. Concomitantly, we reported that humans with homozygous complete lossoffunction mutations in dgat1 have a. Oil in the form of triacylglycerols tags is quantitatively the most important storage form of energy for eukaryotic cells. Dgat1 inhibitor suppresses prostate tumor growth and migration. Combined effects of dgat1 with dpp4 inhibition on glp1. Modeling the mechanism of action of a dgat1 inhibitor using a. After 6 days of incubation at 18 c the tag levels were measured. Lipid droplets form from the endoplasmic reticulum. Proof of mechanism for the dgat1 inhibitor azd7687.
Accelerating the discovery of dgat1 inhibitors through the. To determine the selectivity of this compound, we examined its effects on the activity of various related enzymes expressed in insect cells. Effect of the dgat1 inhibitor pradigastat on triglyceride. Identification and characterization of sebaceous gland atrophysparing dgat1 inhibitors plos one, dec 2019 eric s. Novel dgat1 mutation associated with congenital diarrhea 1231 or other obesityrelated diseases 17. We integrated the analysis of genetic and clinical data from 10,511 individuals in the mount sinai biome biobank to identify genes with lossoffunction variants lofs significantly associated with. Oct 10, 2019 liposomes were loaded with inhibitors by an ammonium sulfate gradient. Identification and characterization of a novel dgat1. Harrison,a daniel bauer,d alina berdichevsky,b xin chen,a rohit duvadie,a benjamin hoogheem,b panos. By this effort, we could map the activity of one group of small molecules to the inhibition of the lipogenic diacylglycerol acyltransferase 1 dgat1 enzyme, which is a known human obesity drug target. Discovery of a potent and selective dgat1 inhibitor with a.
Apexbio dgat1 inhibitordiacylglycerol acyltransferase. 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. Early clinical investigation explored its potential for the treatment of hypertriglyceridemia and nafld. Harrison,a daniel bauer,d alina berdichevsky,b xin chen,a rohit duvadie,a benjamin hoogheem,b panos hatsis,c qian liu,a justin mao,a vasumathy miduturu,a erik rocheford,b frederic zecri,a richard zessis,b rui zheng,a. An isocitrate dehydrogenase2 inhibitor used to treat relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase2 mutation. Molecular biology and biotechnology molecular and cell biochemistry series molecular biology and biotechnology molecular biology and biotechnology molecular biology and biotechnology biochemistry and molecular biology. Chen, jin and meyers, charles and keefe, debbi and yu, jing and sunkara, gangadhar 2017 clinical pharmacokinetics of pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor. Similarly, pharmacological inhibition of dgat1 in enterocytes of rats enhances intestinal fatty acid oxidation and thus reduces energy intake schober et al. Pf04620110 also possesses greater than 100fold selectivity against hdgat2, hacat1, hawat12, hmgat23, mmgat1. A kinase inhibitor used in the treatment of unresectable liver carcinoma and advanced renal carcinoma. Our dgat1 team developed a benzimidazole lead series as exemplified by 1 and 2 in fig.
A, b 3monthold lean dgat122 and wild type mice were fasted overnight, then p. Nov 27, 2019 the dgat1 inhibitor pradigastat is the most widely studied. Diacylglyceride acyltransferase 1 dgat1 is the enzyme that adds the final fatty acid on to a diacylglyceride during triglyceride tg synthesis. 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. Familial chylomicronemia syndrome fcs is a rare lipid disease resulting in severe hypertriglyceridemia caused by complete. To summarize the data from in vitro and clinical pharmacokinetic studies of pradigastat.
Inhibition of triglyceride synthesis as a treatment. A class of diacylglycerol acyltransferase 1 inhibitors. Most of the disclosed dgat1 inhibitors contained a phenylcyclohexane acetic acid moiety that is apparently critical for dgat1 potency. Pharmaceutical companies have developed many novel inhibitors of dgat1, several of which have reached the clinic. T863 is a selective, cellpermeable dgat1 inhibitor that inhibits dgat activity in mouse tissues in vitro. Discovery of a novel class of diacylglycerol acyltransferase.
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. Depletion of the noncentrosomal mtoc protein gm reduced pca cell proliferation and migration. M oleate complexed to bsa and dgat1 inhibitors, and incubated at 37 c for another 2h. We integrated the analysis of genetic and clinical data from 10,511 individuals in the mount sinai biome biobank to identify genes with lossoffunction variants lofs significantly associated with cardiovascular disease cvd. Identification and characterization of sebaceous gland. In this study we assessed the safety, tolerability and tglowering efficacy of the dgat1 inhibitor pradigastat in patients with fcs. The reaction catalyzed by dgat is considered the terminal and only committed step in triglyceride synthesis and to be essential for intestinal absorption i. Us8324241b2 triazolo compounds useful as dgat1 inhibitors. Discovery of pf04620110, a potent, selective, and orally. We demonstrate a synergistic effect on the incretin response with the combination of a dgat1 inhibitor and sitagliptin, a dipeptidyl peptidase.
Supplementary information for successful strategies for. Living organisms often store energy in the form of fat molecules called triglycerides. Effect of the dgat1 inhibitor pradigastat on triglyceride and apob48 levels in patients with familial chylomicronemia syndrome by charles daniel meyers, karine tremblay, ahmed amer, jin chen, liewen jiang and daniel gaudet. However, recent findings prompt concern for dgat1 inhibition in humans because of the severe side effects which include nausea, diarrhea, and vomiting following meals containing fat. Profound methyl effects in drug discovery and a call for new ch.
Objective investigation was conducted to understand the mechanism of action of diacylglycerol acyltransferase 1 dgat1 using small molecules dgat1 inhibitors, compounds k and l. Discovery of a potent and selective dgat1 inhibitor with a piperidinyloxycyclohexanecarboxylic acid moiety, acs medicinal chemistry letters, 2014, 510, 10821087. To further validate the assay for its hitfinding capability and data reproducibility in screening, assay plates with randomly. Disclosed are triazolopyridine compounds of formula i, including pharmaceutically acceptable salts thereof. A growing amount of research has indicated that an exaggerated postprandial circulating tg level is a risk indicator for cardiovascular and metabolic. Targeting diacylglycerol acyltransferase 2 for the treatment. Diglyceride acyltransferase or oacyltransferase, dgat, catalyzes the formation of triglycerides from diacylglycerol and acylcoa.
A population analysis of the dgat1 inhibitor gsk3008356 and its effect on endogenous and meal. Reversible deficits in apical transporter trafficking. Chlorella, a unicellular eukaryotic green alga, has attracted much attention as a potential feedstock for renewable energy production. Consequences of idgat1 deficiency phenocopy findings in wholebody dgat1. Discovery of a potent and selective dgat1 inhibitor with a piperidinyloxycyclohexanecarboxylic acid moiety, acs medicinal chemistry letters, 2014, 5 10, 10821087. 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.
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