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Zeitschrift Fur Naturforschung. C,... Jul 2022Although -2-oxo-4-methyl-3-pentene-1,5-dioic acid (-OMPD) has been identified as a major dicarboxylic acid in tulip tissues, its biosynthetic pathway has not been...
Although -2-oxo-4-methyl-3-pentene-1,5-dioic acid (-OMPD) has been identified as a major dicarboxylic acid in tulip tissues, its biosynthetic pathway has not been elucidated. Herein, -OMPD was isolated from tulip leaves and chemically synthesized. Comparisons of these samples revealed that -OMPD exists as a tautomeric mixture at physiological pH. As a regioisomer of -OMPD, we enzymatically and chemically prepared 4-methylene-2-oxo-glutaric acid (4-MEOG) for the first time. Using these compounds as standards, the occurrence of -OMPD and 4-MEOG in various tissues of the tulip cultivar "Murasakizuisho" was evaluated directly and by 2,4-dinitrophenylhydrazone derivatization. -OMPD was found to be abundant in the aerial tissues, whereas 4-MEOG was almost absent from all tissues. Stability analyses of -OMPD and 4-MEOG revealed that no double bond isomerization occurred at physiological pH, suggesting that enzyme systems are responsible for -OMPD biosynthesis in tulip tissues.
Topics: Alkenes; Glutarates; Oxotremorine; Tulipa
PubMed: 35245421
DOI: 10.1515/znc-2021-0282 -
Current Cardiology Reports Sep 2023To provide an updated review of bempedoic acid's clinical application in lowering LDL-C in the setting of statin intolerance and the recent findings in the CLEAR... (Review)
Review
PURPOSE OF REVIEW
To provide an updated review of bempedoic acid's clinical application in lowering LDL-C in the setting of statin intolerance and the recent findings in the CLEAR Outcomes trial as well as summarize and synthesize the current state of knowledge regarding bempedoic acid while providing an in-depth analysis of the drug's pharmacological properties, mechanism of action, clinical trials, safety, and efficacy.
RECENT FINDINGS
The CLEAR Outcomes trial has provided evidence to support bempedoic acid as a viable alternative to statins for the primary and secondary prevention of cardiovascular disease. Bempedoic acid is a promising treatment option for patients with hypercholesterolemia who are unable to tolerate statin therapy or require additional LDL-C reduction in the treatment of cardiovascular disease, with the newest lipid-lowering cardiovascular outcomes trials expanding on their generalizability particularly in the inclusion of women.
Topics: Humans; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Cardiovascular Diseases; Hypercholesterolemia; Dicarboxylic Acids; Fatty Acids
PubMed: 37405598
DOI: 10.1007/s11886-023-01911-9 -
Drug Design, Development and Therapy 2021Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD)... (Review)
Review
Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD) and for primary prevention in individuals with heterozygous familial hypercholesterolemia (HeFH) by the United States Food and Drug Administration. Pooled data from the phase III clinical trials, CLEAR Harmony and CLEAR Wisdom, have demonstrated the safety and efficacy of bempedoic acid with regard to lowering of low-density lipoprotein cholesterol (LDL-C) in patients with HeFH as an adjunct or alternative to currently existing lipid-lowering therapies. CLEAR Outcomes is a cardiovascular outcomes trial that is currently underway that will provide additional insight as to where bempedoic acid will fit into treatment regimens among the non-statin lipid-lowering therapy options. Patients who might particularly benefit from bempedoic acid are those with HeFH and those unable to take adequate doses of statins or take any statin therapy altogether who need additional LDL-C lowering. In this review, we will discuss the profile of bempedoic acid from its design, development, and its place in therapy for the management of LDL-C for the purposes of ASCVD prevention.
Topics: Animals; Anticholesteremic Agents; Atherosclerosis; Cholesterol, LDL; Dicarboxylic Acids; Drug Design; Drug Development; Fatty Acids; Humans; Hyperlipoproteinemia Type II
PubMed: 34007155
DOI: 10.2147/DDDT.S251865 -
Expert Review of Cardiovascular Therapy Jul 2020Although several lipid-lowering drugs are available, they are not sufficient for some patients. Bempedoic acid is a small molecule adenosine triphosphate-citrate lyase...
INTRODUCTION
Although several lipid-lowering drugs are available, they are not sufficient for some patients. Bempedoic acid is a small molecule adenosine triphosphate-citrate lyase inhibitor indicated for the treatment of adults with hypercholesterolemia.
AREAS COVERED
We performed a systematic review of the literature using PubMed database, and the following keywords were used: 'bempedoic acid,' 'hypercholesterolemia,' and 'adenosine triphosphate citrate lyase.' The chemical property, mechanism of action, pharmacokinetics, clinical efficacy, and safety of bempedoic acid are introduced in this paper.
EXPERT OPINION
Bempedoic acid can modulate the metabolism of cholesterol. Clinical trials indicated that bempedoic acid could significantly reduce low-density lipoprotein cholesterol levels. Bempedoic acid was well tolerated.
Topics: Cholesterol; Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia; Hypolipidemic Agents; Treatment Outcome
PubMed: 32532162
DOI: 10.1080/14779072.2020.1782744 -
Indian Heart Journal Mar 2024Despite numerous improvements in the management of acute coronary syndrome(ACS), it is a major cause of mortality in India. Lipids play a critical role in pathogenesis... (Review)
Review
Despite numerous improvements in the management of acute coronary syndrome(ACS), it is a major cause of mortality in India. Lipids play a critical role in pathogenesis of ACS and reduction of lipid parameters plays a pivotal role in secondary prevention. High total cholesterol and high low-density lipoprotein(LDL) are the major lipid abnormalities globally as well as in Indians. Among all the lipid parameters, LDL is the primary target of lipid-lowering therapies across the globe. High-dose statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bempedoic acid are recommended therapies for LDL reduction in ACS patients. Statins have pleiotropic effects on the modulation of thrombogenesis, endothelial dysfunction, and myocardial protection. Multiple randomised controlled trials and meta-analyses have shown that the use of high-dose statin has significant benefits in ACS. LDL reduction goal is < 55 mg/dl or at least 50 % reduction from the baseline regardless of age or gender. Non-fasting LDL should be measured soon after the ACS as it varies minimally with food intake. The first line of therapy after ACS is to advise lifestyle modifications, combination therapy including high-dose statin with ezetimibe, and evaluation after 4-6 weeks of the index event. If the goal is not achieved then PCSK 9 inhibitors or Bempedoic acid should be used in combination with statins and ezetimibe to reduce recurrent ischaemic events. Despite the proven effect of these lipid-lowering therapies, undertreatment is still a big hurdle across the globe. Prohibitive costs, adverse effects, medication non-adherence, variation in health practice in different countries, and clinical inertia to prescribe this medication by physicians are the main reasons for the undertreatment.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Acute Coronary Syndrome; Cholesterol, LDL; Ezetimibe; Dyslipidemias; Anticholesteremic Agents; Proprotein Convertase 9; Dicarboxylic Acids; Fatty Acids
PubMed: 38307382
DOI: 10.1016/j.ihj.2024.01.011 -
Future Cardiology Sep 2020Bempedoic acid (ETC-1002) is a novel, first-in-class, oral, small molecule that inhibits cholesterol biosynthesis in the same pathway as statins, thereby lowering... (Review)
Review
Bempedoic acid (ETC-1002) is a novel, first-in-class, oral, small molecule that inhibits cholesterol biosynthesis in the same pathway as statins, thereby lowering low-density lipoprotein cholesterol (LDL-C) by upregulating LDL receptors. Preclinical and completed Phase II and III clinical trials have demonstrated promising results regarding its safety and efficacy across a variety of patient characteristics including statin intolerance and on a background of lipid-lowering therapy. Bempedoic acid is currently being evaluated in a cardiovascular outcomes trial to evaluate its effect on major cardiovascular events in patients with or at high risk for cardiovascular disease and with statin intolerance. In this review, we will discuss the history and development of bempedoic acid, relevant clinical trials, and its potential role as a lipid-lowering medication in the context of other currently available lipid-lowering therapies.
Topics: Anticholesteremic Agents; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 32463301
DOI: 10.2217/fca-2020-0016 -
Giornale Italiano Di Cardiologia (2006) Apr 2021The efficacy and safety of bempedoic acid, including the occurrence of muscle-related adverse events, have been addressed by phase 2 and phase 3 clinical trials. Phase 3... (Clinical Trial)
Clinical Trial
The efficacy and safety of bempedoic acid, including the occurrence of muscle-related adverse events, have been addressed by phase 2 and phase 3 clinical trials. Phase 3 clinical trials demonstrated that in patients with atherosclerotic cardiovascular disease and/or familial hypercholesterolemia who were treated with statins at maximum tolerated dose, with or without further lipid-lowering drugs, bempedoic acid treatment was associated with a significant reduction in low-density lipoprotein cholesterol in different groups of patients with a favorable safety profile. An ongoing phase 3 study is currently evaluating the effect of longer-term (median duration of 3-4 years) treatment with bempedoic acid on the incidence of cardiovascular events.
Topics: Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia
PubMed: 33847314
DOI: 10.1714/3582.35672 -
Expert Opinion on Drug Metabolism &... Sep 2021: Bempedoic acid is a first-in-class low-density lipoprotein cholesterol (LDL-C) lowering agent which offers an important opportunity for further LDL-C lowering in... (Review)
Review
: Bempedoic acid is a first-in-class low-density lipoprotein cholesterol (LDL-C) lowering agent which offers an important opportunity for further LDL-C lowering in statin-intolerant patients or in patients requiring further LDL-C reduction despite maximally tolerated statin therapy.: In this review, we examined the pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of bempedoic acid, based on randomized clinical phase III clinical studies and their meta-analyses.: Unlike statins, bempedoic acid is administered as a prodrug and is converted to active form by a liver-specific enzyme. For the liver-specific mechanism of action, bempedoic acid has the potential to reduce the risk of muscle-related adverse events which can limit the utilization and effectiveness of statin therapy.
Topics: Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Randomized Controlled Trials as Topic
PubMed: 34197267
DOI: 10.1080/17425255.2021.1951222 -
American Journal of Health-system... Jan 2021An update on clinical development of a first-in-class oral medication for adjunctive cholesterol lowering in high-risk patients with persistent elevation of low-density... (Review)
Review
PURPOSE
An update on clinical development of a first-in-class oral medication for adjunctive cholesterol lowering in high-risk patients with persistent elevation of low-density lipoprotein cholesterol (LDL-C) despite statin therapy is reviewed.
SUMMARY
Despite the proven efficacy of statin therapy, many patients cannot reach LDL-C goals with statins alone, largely due to inadequate response or intolerance. Nonstatin treatment options to reduce LDL-C include ezetimibe, bile acid sequestrants, and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors; however their use has been limited by modest clinical benefit or high treatment costs. Novel nonstatin treatments are in development to further address the needs of this population. Bempedoic acid is a first-in-class oral adenosine triphosphate (ATP) citrate lyase inhibitor being evaluated as an additional treatment option for high-risk patients requiring further reduction in LDL-C. Bempedoic acid has been evaluated in multiple phase 2 and phase 3 trials as monotherapy or for use in combination with ezetimibe and/or statin therapy. Treatment with bempedoic acid has been demonstrated to result in significant reductions in LDL-C and several other cardiovascular risk markers without the myalgia associated with statin therapy.
CONCLUSION
Bempedoic acid, used alone or with ezetimibe in a fixed-dose combination formulation, may be an effective alternative to current guideline-recommended nonstatin therapies in patients who do not attain adequate LDL-C lowering with maximally tolerated statin therapy and in statin-intolerant patients at risk for atherosclerotic cardiovascular disease.
Topics: Anticholesteremic Agents; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9
PubMed: 33399194
DOI: 10.1093/ajhp/zxaa352 -
ChemistryOpen May 2021Photodecarboxylase from Chlorella variabillis (CvFAP) is one of the three known light-activated enzymes that catalyzes the decarboxylation of fatty acids into the...
Photodecarboxylase from Chlorella variabillis (CvFAP) is one of the three known light-activated enzymes that catalyzes the decarboxylation of fatty acids into the corresponding C1-shortened alkanes. Although the substrate scope of CvFAP has been altered by protein engineering and decoy molecules, it is still limited to mono-fatty acids. Our studies demonstrate for the first time that long chain dicarboxylic acids can be converted by CvFAP. Notably, the conversion of dicarboxylic acids to alkanes still represents a chemically very challenging reaction. Herein, the light-driven enzymatic decarboxylation of dicarboxylic acids to the corresponding (C2-shortened) alkanes using CvFAP is described. A series of dicarboxylic acids is decarboxylated into alkanes in good yields by means of this approach, even for the preparative scales. Reaction pathway studies show that mono-fatty acids are formed as the intermediate products before the final release of C2-shortened alkanes. In addition, the thermostability, storage stability, and recyclability of CvFAP for decarboxylation of dicarboxylic acids are well evaluated. These results represent an advancement over the current state-of-the-art.
Topics: Alkanes; Biocatalysis; Biodegradable Plastics; Carboxy-Lyases; Catalytic Domain; Chlorella; Decarboxylation; Dicarboxylic Acids; Fatty Acids; Light; Molecular Docking Simulation; Photochemical Processes; Protein Binding; Protein Engineering; Structure-Activity Relationship
PubMed: 33945237
DOI: 10.1002/open.202100039