Synthesis and biological evaluation of novel thienopyrimidine derivatives as diacylglycerol acyltransferase 1 (DGAT-1) inhibitors

Hong, Dong Jin; Jung, Seung Hyun; Kim, Jisook; Jung, Danbee; Ahn, Young Gil; Suh, Kwee Hyun; Min, Kyung Hoon

doi:10.1080/14756366.2019.1693555

Cited by 13 publications

(4 citation statements)

References 21 publications

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“…Currently, at least one promising agent (IONIS DGAT2Rx) from this drug group has completed phase II clinical trials. Being a hepatoprotectant, it is not a classic hyperglycemic drug, but it indirectly affects glycemia by increasing insulin sensitivity and protecting islet β-cells ( Zhu et al, 2019 ; Hong et al, 2020 ).…”

Section: Novel Drug Targetsmentioning

confidence: 99%

Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales

et al. 2022

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Type 2 diabetes mellitus (T2DM) continues to be a substantial medical problem due to its increasing global prevalence and because chronic hyperglycemic states are closely linked with obesity, liver disease and several cardiovascular diseases. Since the early discovery of insulin, numerous antihyperglycemic drug therapies to treat diabetes have been approved, and also discontinued, by the United States Food and Drug Administration (FDA). To provide an up-to-date account of the current trends of antidiabetic pharmaceuticals, this review offers a comprehensive analysis of the main classes of antihyperglycemic compounds and their mechanisms: insulin types, biguanides, sulfonylureas, meglitinides (glinides), alpha-glucosidase inhibitors (AGIs), thiazolidinediones (TZD), incretin-dependent therapies, sodium-glucose cotransporter type 2 (SGLT2) inhibitors and combinations thereof. The number of therapeutic alternatives to treat T2DM are increasing and now there are nearly 60 drugs approved by the FDA. Beyond this there are nearly 100 additional antidiabetic agents being evaluated in clinical trials. In addition to the standard treatments of insulin therapy and metformin, there are new drug combinations, e.g., containing metformin, SGLT2 inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors, that have gained substantial use during the last decade. Furthermore, there are several interesting alternatives, such as lobeglitazone, efpeglenatide and tirzepatide, in ongoing clinical trials. Modern drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists, DPP4 inhibitors and SGLT2 inhibitors have gained popularity on the pharmaceutical market, while less expensive over the counter alternatives are increasing in developing economies. The large heterogeneity of T2DM is also creating a push towards more personalized and accessible treatments. We describe several interesting alternatives in ongoing clinical trials, which may help to achieve this in the near future.

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Section: Novel Drug Targetsmentioning

confidence: 99%

Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales

et al. 2022

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“…Despite the progress in the development of chemotherapeutic agents, several new target-specific and improved anticancer agents with minimum/no side effects are essential to tackle drug resistance. 46–48…”

Section: Introductionmentioning

confidence: 99%

“…Despite the progress in the development of chemotherapeutic agents, several new targetspecific and improved anticancer agents with minimum/no side effects are essential to tackle drug resistance. [46][47][48] According to the U.S. Food and Drug Administration (FDA) database, nearly 60% of small-molecule drugs are nitrogencontaining heterocycles. 49 Incorporation of nitrogen atoms or N-based heterocycles in a pharmacophore such as a fused pyran may not only increase its water solubility but also enhance the binding to a variety of biological targets such as enzymes and receptors.…”

Section: Introductionmentioning

confidence: 99%

Novel fused pyran derivatives induce apoptosis and target cell cycle progression in anticancer efficacy against multiple cell lines

Fabitha,

Kallingal,

Maciejewska

et al. 2024

New J. Chem.

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“…Fatty acids and dietary lipid composition and fasting period can largely affect lipid metabolism [ 15 – 17 ]. For example, when the anti-hypertriglyceridemia effects of diacylglycerol acyltransferase-1 inhibitors were investigated in mice, lipid sources, dosage, and the fasting period before the OLTT were not uniform [ 18 – 20 ] ( Table 1 ). Furthermore, postprandial hyperglycemia has been identified as another well-known risk factor for coronary diseases, but its evaluation in mice and human models has been generally standardized [ 21 ], unlike in postprandial hyperlipidemia testing.…”

Section: Introductionmentioning

confidence: 99%

Evaluating the appropriate oral lipid tolerance test model for investigating plasma triglyceride elevation in mice

Ochiai

2020

PLoS ONE

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The oral lipid tolerance test (OLTT) has been known to assess intestinal fat metabolism and whole-body lipid metabolism, but rodent models for OLTT are not yet established. Differences in OLTT methodology preclude the generation of definitive results, which may cause some confusion about the anti-hypertriglyceridemia effects of the test materials. To standardize and generate more appropriate methodology for the OLTT, we examined the effects of mice strain, dietary lipid sources, fasting period, and gender on lipid-induced hypertriglyceridemia in mice. First, lipid-induced hypertriglyceridemia was more strongly observed in male ddY mice than in C57BL/6N or ICR mice. Second, the administration of olive and soybean oils remarkably represented lipid-induced hypertriglyceridemia. Third, fasting period before the OLTT largely affected the plasma triglyceride elevation. Fasting for 12 h, but less than 48 h, provoked lipid-induced hypertriglyceridemia. Fourth, we explored the suppressive effects of epigallocatechin gallate (EGCG), a green tea polyphenol, on lipid-induced hypertriglyceridemia. The administration of 100 mg/kg of EGCG suppressed lipid-induced hypertriglyceridemia and intestinal lipase activity. Fifth, EGCG-induced suppressive effects were observed after lipid-induced hypertriglyceridemia was observed in male mice, but not in female mice. Lastly, lipid-induced hypertriglyceridemia could be more effectively induced in mice fed a high-fat diet for 1 week before the OLTT. These findings indicate that male ddY mice after 12 h fasting displayed marked lipid-induced hypertriglyceridemia in response to soybean oil. Hence, the defined experiment condition may be a more appropriate OLTT model for evaluating lipid-induced hypertriglyceridemia.

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Synthesis and biological evaluation of novel thienopyrimidine derivatives as diacylglycerol acyltransferase 1 (DGAT-1) inhibitors

Cited by 13 publications

References 21 publications

Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales

Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales

Novel fused pyran derivatives induce apoptosis and target cell cycle progression in anticancer efficacy against multiple cell lines

Evaluating the appropriate oral lipid tolerance test model for investigating plasma triglyceride elevation in mice

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