Pdf modeling the mechanism of action of a dgat1 inhibitor. Intestinetargeted dgat1 inhibition improves obesity and insulin resistance without skin aberrations in mice naoto tsuda1,2, shin kumadaki1, chika higashi1, makoto ozawa1, mikihiko shinozaki1, yutaka. Triglyceride synthesis by dgat1 protects adipocytes from lipid. In summary, we have described the discovery of a novel series of dgat1 inhibitors in the benzimidazole class with a piperdinyloxycyclohexanecarboxylic acid moiety. Farese, jr abstractbecause the ability to make triglycerides is. Potent dgat1 inhibitors in the benzimidazole class with a. Apexbio dgat1 inhibitordiacylglycerol acyltransferase. Synthesis optimization and sar exploitation enabled the identification of s10, a suitable candidate for. Discovery of a novel class of diacylglycerol acyltransferase. Origin and evolution of retinoid isomerization machinery. Erythromycin modification that improves its acidic stability.
Szeto, 1 xiaorui yao, 1 jianying xiao, 1 shirley chen, 1 jinqi liu, 1 marga. Intestinetargeted dgat1 inhibition improves obesity and insulin resistance without skin aberrations in mice naoto tsuda1,2, shin kumadaki1, chika higashi1, makoto ozawa1, mikihiko shinozaki1, yutaka kato1, koutarou hoshida1, satomi kikuchi1, yoshihisa nakano1, yoshihiro ogawa2, shoji furusako1 1discovery research, mochida pharmaceutical company limited, shizuoka, japan, 2department of. T863, a potent dgat1 inhibitor acting on the acylcoa binding site of dgat1. Inhibition of triglyceride synthesis as a treatment strategy. Human pharmacokinetics and safety study of gsk3008356, a selective dgat1 inhibitor, in healthy volunteers. We report the design and synthesis of a series of novel dgat1 inhibitors in the benzimidazole class with a pyridyloxycyclohexanecarboxylic acid moiety. Treatment of human skeletal muscle cells with inhibitors of. Findings from genetically modified mice as well as pharmacological studies suggest that inhibition of dgat1 is a promising strategy for the treatment of obesity and type 2 diabetes. Although this study focused on dgat1, activity of either dgat enzyme was sufficient to protect the adipocyte er from lipotoxic stress under basal conditions. Pf04620110 is a potent, selective and orallybioavailable inhibitor of diacylglycerol acyltransferase 1 dgat1, an enzyme catalyzing the final committed step in the biosynthesis of triglycerides, that inhibits dgat1 with values of 50% inhibition concentration ic50 of 19 nm and 8 nm in human and ht29 cells respectively. Collectively, we clearly demonstrated that h2003 and 005 are a novel class of dgat2selective inhibitors.
T863, a potent dgat1 inhibitor acting on the acylcoa. Pf04620110 also possesses greater than 100fold selectivity against hdgat2, hacat1, hawat12, hmgat23, mmgat1. Triglyceride synthesis by dgat1 protects adipocytes from. Nov 27, 2019 the dgat1 inhibitor pradigastat is the most widely studied. Proof of mechanism for the dgat1 inhibitor azd7687.
Inhibition of triglyceride synthesis as a treatment. Intestinetargeted dgat1 inhibition improves obesity and insulin resistance without skin aberrations in mice article pdf available in plos one 911. 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. Pf04620110 also possesses greater than 100fold selectivity. Assay development and screening of human dgat1 inhibitors. Following a single dose of a selective pharmacological inhibitor of dgat1, pf04620110, a dosedependent inhibition of tg and vitamin a absorption postprandially was demonstrated in rodents and human subjects. It is a group of intertwined maladies that includes obesity, hypertriglyceridemia, hypertension, nonalcoholic fatty liver. Suppression of diacylglycerol acyltransferase2 dgat2, but. Pdf intestinetargeted dgat1 inhibition improves obesity. In summary, a novel series of mgat2 inhibitors have been identified.
Dgat1 inhibitor induced differential fatty acid composition in rats and humans following a mixed meal. Indeed, dgat1 inhibitors had significant pharmacologic effects, including decreased tag, which were consistent with the dgat1 knockout mice. Modeling the mechanism of action of a dgat1 inhibitor using a causal reasoning platform article pdf available in plos one 611. Results from a firsttimeinhuman singledose study inhibition of diacylglycerol. The prolonged incretin signal produced by the combination of dppiv inhibitor sitagliptin and pf0462 0110 is in agreement with a published study using a different dgat1 inhibitor. Pdf on jan 10, 2017, sanjay kumar and others published a novel acylcoa. A fluorescencebased assay for characterization and. P7435 has been developed by the nce research division of pel for the management of metabolic disorders. Metabolic syndrome is an everincreasing health problem among the worlds population. Diacylglycerol acyltransferase1 dgat1 inhibition perturbs. Modeling the mechanism of action of a dgat1 inhibitor. Farese, jr abstractbecause the ability to make triglycerides is essential for the accumulation of adipose tissue, inhibition of triglyceride synthesis may ameliorate obesity and its related medical consequences.
Either dgat1 or dgat2 inhibitor alone did not attain this effect. Dgat1 is a triglyceride biosynthetic enzyme with a possible role in metabolic disorders. Apexbio pf04620110dgat1 inhibitor,potent and selective. The role of diacylglycerol acyltransferase dgat 1 and 2 in. 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. However, it remains unclear whether a pan inhibitor for both dgat enzymes is more beneficial than isoform. This is a novel, potent and highly selective, oral diacylglycerolacyltransferase 1 dgat1 inhibitor. Targeting diacylglycerol acyltransferase 2 for the treatment.
The diacylglycerol acyltransferase dgat 1 inhibitor a922500 was shown to effectively reduce postprandial serum triglyceride levels in rodents at concentrations of 0. Inhibition of triglyceride synthesis as a treatment strategy for obesity lessons from dgat1deficient mice hubert c. In this study we assessed the safety, tolerability and tglowering efficacy of the dgat1 inhibitor pradigastat in patients with fcs. Dgat1 inhibitor suppresses prostate tumor growth and migration. The reaction catalyzed by dgat is considered the terminal and only committed step in triglyceride synthesis and to be essential for intestinal absorption i. Dgat1 inhibitors have potential for the treatment of obesity and a number of dgat1 inhibitors are in clinical trials for this indication. Either dgat1 or dgat2 inhibitor alone did not attain. P dec 02, 2011 here we characterize a tool dgat1 inhibitor compound, t863.
Pf04620110 is a potent, selective and orallybioavailable inhibitor of diacylglycerol acyltransferase 1 dgat1, an enzyme catalyzing the final committed step in the biosynthesis of triglycerides, that. 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. Targeting diacylglycerol acyltransferase 2 for the. When compared to the control, the treatment with a dgat1 inhibitor significantly reduced the levels of. The dgat1 inhibitor pradigastat is the most widely studied. Request pdf dgat1 inhibitors as antiobesity and antidiabetic agents since 2008, significant advances have been made in understanding the role of diacylglycerol acyl transferase1 dgat1 in. Compound a, described in the patent application from the japan.
Treatment with dgat2 inhibitor in mice with cardiacspecific dgat1 deficiency prevents tg accumulation in the heart during 5week high fat diet. In the intestine, dgat1 is one of the acyltransferases responsible for the reesterficiation of dietary tg. Following a single dose of a selective pharmacological inhibitor of dgat1, pf04620110, a dose. The discovery of pf04620110 has been reported previously and is a potent and selective small molecule inhibitor of dgat1 with 100fold selectivity vs. Furthermore, pf04620110 was able to dose responsively increase glp1 and pyy, but blunt gip at all doses of pf04620110 during lipid challenge. Food was removed from each cage 24 hours prior to administration of dgat1 inhibitor. Because of conflicting reports about the development of glucose intolerance in adipoq. These results suggest a922500 may have beneficial effects in reducing the risk of cardiovascular disease. 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. Clinical development of azd7687, 15 a novel dgat1 inhibitor has recently been stopped due to intolerable side effects.
Lin, 1, dunlu chen, 1 zhu shen, 1 lei zhu, 1 xuesong ouyang, 2 aurawan vongs, 1 yanqing kan, 1 john m. Pharmacological inhibition to examine the role of dgat1 in. Request pdf proof of mechanism for the dgat1 inhibitor azd7687. Pharmaceutical companies have developed many novel inhibitors of dgat1, several of which have reached the clinic. Dgat1 and dgat2 specific activities in differentiated 3t3l1 adipocytes were determined by 14 coleic acid incorporation into tg in presence of inhibitors. P dgat1 inhibitor was shown to cause weight loss, reduction in liver tag, and depletion of serum tag following a lipid challenge in a dosedependent manner, recapturing the major phenotype of dgat1 knockout mice. Diacylglycerol acyltransferases dgat 1 and 2 catalyse the final step in triacylglycerol tag synthesis, the esterification of fatty acylcoa to. To summarize the data from in vitro and clinical pharmacokinetic studies of pradigastat.
Erythromycin modification that improves its acidic. This novel series possesses significantly improved selectivity. As the metabolic phenotypes of dgat1 null mice are lost when dgat1 is reintroduced into the intestine, we raised a hypothesis that the intestinetargeted dgat1 inhibitor would improve metabolic disorders. Effect of the dgat1 inhibitor pradigastat on triglyceride. 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. 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.
However, the degree of dgat1 inhibition required for metabolic benefits is unclear. However, development of several dgat1 inhibitors has been hampered due to unacceptable gastrointestinal gi tolerability observed in clinical trials. Subsequently blood and jejunum were removed for lipomics analysis. P7435 has been developed by the nce research division of pel for the management of metabolic disorders such as lipid abnormalities and diabetes. Generally, when ad is conjugated to drugs, it functions to increase the drugs hydrophobicity which can enable the drug to bind to tissue more. Effect of the dgat1 inhibitor pradigastat on triglyceride and.
Dgat1 inhibitors as antiobesity and antidiabetic agents. 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. Pharmacological inhibition of diacylglycerol acyltransferase. This work determined whether the intestinetargeted dgat1 inhibitor could improve obesity and insulin resistance without skin aberrations in mice. Early clinical investigation explored its potential for the treatment of hypertriglyceridemia and 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.
Jane lee for technical assistance, and gary howard for manuscript editing. Interestingly, when pedf treatment was combined with addition of dgat1 inhibitor, cafs showed increased lipid catabolism with a significant decrease in the number of lds per cell compared to treatment with pedf alone 2. Circulating plasma tg levels were measured at 0, 2, 4, and 6hr time points. This series of compounds abolish the acat1 offtarget activity associated with the earlier pyridyloxycyclohexanecarboxylic acid series. This response was further augmented with dgat1 inhibitor. Finally, combined treatment of h2003 or 005 with a dgat1 inhibitor effectively suppressed oleateinduced ld formation in 3t3l1 preadipose cells. Identification and design of a novel series of mgat2. Intestinetargeted dgat1 inhibition improves obesity and. M, and higher aqueous solubility and free fraction in plasma as compared. Dgat2 inhibition alters aspects of triglyceride metabolism.
This novel series possesses significantly improved selectivity against the a 2a receptor, no acat1 offtarget activity at 10. In particular, compound 11a is a potent dgat1 inhibitor with excellent selectivity against acat1. Here we show that partial dgat1 deficiency in mice. Suppression of diacylglycerol acyltransferase2 dgat2. A nfs and cafs were treated with dgat1 inhibitor dgat1in. Dgat1 processes diacylglycerol to triglycerides in the final step of resynthesis for the absorption of fat across the intestine. Diacylglycerol acyltransferase dgat, of which there are two isoforms dgat1 and dgat2, catalyzes the final step in triglyceride synthesis. Discovery of a potent and selective dgat1 inhibitor with a. Furthermore, pf04620110 was able to dose responsively increase glp1 and pyy, but blunt gip at all. Additional studies performed address the molecular mechanism by with pharmacological inhibition of dgat1 results in increased gut peptide secretion. Modeling the mechanism of action of a dgat1 inhibitor using a.
In humans, the dppiv inhibitor vildagliptin singularly increased active glp1 and gip circulation while decreasing pyy, glucose and increasing insulin in the. Pharmacological inhibition of diacylglycerol acyltransferase1 and. Recently, a highly potent dgat1 inhibitor was shown to cause weight loss, reduction in liver tag, and depletion of serum tag following a lipid challenge in a dosedependent manner, recapturing the major. Cells were pretreated for 30 min with 5 m inhibitors, cells were pulse labeled with 14 coleic acid 50 cimol for 3 h in presence of inhibitors. The mice were administered compound 16 subcutaneously and oral dgat1 inhibitor either alone or in combination at 18 hr and 1 hr prior to the p407 injection.
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