(2E)-2,3-Dehydroxy Atorvastatin

For research use only. Not for therapeutic Use.

  • CAT Number: R031287
  • CAS Number: 1105067-93-3
  • Molecular Formula: C₃₃H₃₃FN₂O₄
  • Molecular Weight: 540.62
  • Purity: ≥95%
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Catalog Number R031287
CAS Number 1105067-93-3
Synonyms

Atorvastatin 3-Deoxyhept-2E-Enoic Acid

Molecular Formula C₃₃H₃₃FN₂O₄
Purity ≥95%
Target Drug Metabolite
Storage -20°C
IUPAC Name (E,5S)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-5-hydroxyhept-2-enoic acid
InChI InChI=1S/C33H33FN2O4/c1-22(2)31-30(33(40)35-26-12-7-4-8-13-26)29(23-10-5-3-6-11-23)32(24-16-18-25(34)19-17-24)36(31)21-20-27(37)14-9-15-28(38)39/h3-13,15-19,22,27,37H,14,20-21H2,1-2H3,(H,35,40)(H,38,39)/b15-9+/t27-/m0/s1
InChIKey MBPXXTUUUBBIRF-LQYYAUOTSA-N
SMILES CC(C)C1=C(C(=C(N1CCC(CC=CC(=O)O)O)C2=CC=C(C=C2)F)C3=CC=CC=C3)C(=O)NC4=CC=CC=C4
Reference

{1]. Trials. 2020 Oct 30;21(1):902. doi: 10.1186/s13063-020-04840-y.<br />
Atorvastatin and Aspirin as Adjuvant Therapy in Patients with SARS-CoV-2 Infection: A structured summary of a study protocol for a randomised controlled trial.<br />
Ghati N(1), Roy A(1), Bhatnagar S(2), Bhati S(1), Bhushan S(1), Mahendran M(1), Thakur A(1), Tiwari P(3), Dwivedi T(4), Mani K(5), Gupta R(6), Mohan A(3), Garg R(2), Saxena A(1), Guleria R(3), Deepti S(7).<br />
Author information: (1)Department of Cardiology, All India Institute of Medical Sciences (AIIMS), Ansari Nagar East, New Delhi, 110029, India. (2)Department of Onco-Anaesthesia, Dr. B.R.A Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences (AIIMS), New Delhi, India. (3)Department of Pulmonary Medicine and Sleep Disorders, All India Institute of Medical Sciences (AIIMS), New Delhi, India. (4)Department of Laboratory Medicine, National Cancer Institute (Jhajjar, Haryana), All India Institute of Medical Sciences (AIIMS), New Delhi, India. (5)Department of Biostatistics, All India Institute of Medical Sciences (AIIMS), New Delhi, India. (6)Department of Laboratory Oncology, Dr. B.R.A Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences (AIIMS), New Delhi, India. (7)Department of Cardiology, All India Institute of Medical Sciences (AIIMS), Ansari Nagar East, New Delhi, 110029, India. [email protected].<br />
OBJECTIVES: To assess the impact of adding statin (atorvastatin) and/or aspirin on clinical deterioration in patients infected with SARS-CoV-2 who require hospitalisation. The safety of these drugs in COVID-19 patients will also be evaluated. TRIAL DESIGN: This is a single-centre, prospective, four-arm parallel design, open-label, randomized control trial. PARTICIPANTS: The study will be conducted at National Cancer Institute (NCI), Jhajjar, Haryana, which is a part of All India Institute of Medical Sciences (AIIMS), New Delhi, and has been converted into a dedicated COVID-19 management centre since the outbreak of the pandemic. All RT-PCR confirmed cases of SARS-CoV-2 infection with age &ge; 40 years and &lt; 75 years requiring hospital admission (patients with WHO clinical improvement ordinal score 3 to 5) will be included in the trial. Written informed consent will be taken for all recruited patients. Patients with a critical illness (WHO clinical improvement ordinal score &gt; 5), documented significant liver disease/dysfunction (aspartate transaminase [AST] / alanine aminotransferase [ALT] &gt; 240), myopathy and rhabdomyolysis (creatine phosphokinase [CPK] &gt; 5x normal), allergy or intolerance to statins or aspirin, prior statin or aspirin use within 30 days, history of active gastrointestinal bleeding in past three months, coagulopathy, thrombocytopenia (platelet count &lt; 100000/ dl), pregnancy, active breastfeeding, or inability to take oral or nasogastric medications will be excluded. Patients refusing to give written consent and taking drugs that are known to have a significant drug interaction with statin or aspirin [including cyclosporine, HIV protease inhibitors, hepatitis C protease inhibitor, telaprevir, fibric acid derivatives (gemfibrozil), niacin, azole antifungals (itraconazole, ketoconazole), clarithromycin and colchicine] will also be excluded from the trial. INTERVENTION AND COMPARATOR: In this study, the benefit and safety of atorvastatin (statin) and/or aspirin as adjuvant therapy will be compared with the control group receiving usual care for management of COVID-19. Atorvastatin will be prescribed as 40 mg oral tablets once daily for ten days or until discharge, whichever is earlier. The dose of aspirin will be 75 mg once daily for ten days or until discharge, whichever is earlier. All other therapies will be administered according to the institute&#39;s COVID-19 treatment protocol and the treating physician&#39;s clinical judgment. MAIN OUTCOMES: All study participants will be prospectively followed up for ten days or until hospital discharge, whichever is longer for outcomes. The primary outcome will be clinical deterioration characterized by progression to WHO clinical improvement ordinal score &ge; 6 (i.e., endotracheal intubation, non-invasive mechanical ventilation, pressor agents, renal replacement therapy, ECMO requirement, and mortality). The secondary outcomes will be change in serum inflammatory markers (C-reactive protein and Interleukin-6), Troponin I, and creatine phosphokinase (CPK) from time zero to 5th day of study enrolment or 7th day after symptom onset, whichever is later. Other clinical outcomes that will be assessed include progression to Acute Respiratory Distress Syndrome (ARDS), shock, ICU admission, length of ICU admission, length of hospital admission, and in-hospital mortality. Adverse drug effects like myalgia, myopathy, rhabdomyolysis, hepatotoxicity, and bleeding will also be examined in the trial to assess the safety of the interventions. RANDOMISATION: The study will use a four-arm parallel-group design. A computer-generated permuted block randomization with mixed block size will be used to randomize the participants in a 1:1:1:1 ratio to group A (atorvastatin with conventional therapy), group B (aspirin with conventional therapy), group C (aspirin + atorvastatin with conventional therapy), and group D (control; only conventional therapy). BLINDING (MASKING): The study will be an open-label trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): As there is no existing study that has evaluated the role of aspirin and atorvastatin in COVID-19 patients, formal sample size calculation has not been done. Patients satisfying the inclusion and exclusion criteria will be recruited during six months of study period. Once the first 200 patients are included in each arm (i.e., total 800 patients), the final sample size calculation will be done on the basis of the interim analysis of the collected data. TRIAL STATUS: The institutional ethical committee has approved the study protocol (Protocol version 3.0 [June 2020]). Participant recruitment starting date: 28th July 2020 Participant recruitment ending date: 27th January 2021 Trial duration: 6 months TRIAL REGISTRATION: The trial has been prospectively registered in Clinical Trial Registry – India (ICMR- NIMS): Reference no. CTRI/2020/07/026791 (registered on 25 July 2020)]. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.<br />
DOI: 10.1186/s13063-020-04840-y PMCID: PMC7598224 PMID: 33126910 [Indexed for MEDLINE]<br />
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[2]. Liver Int. 2019 Nov;39(11):2082-2093. doi: 10.1111/liv.14209. Epub 2019 Sep 10.<br />
CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients.<br />
Pockros PJ(1), Fuchs M(2), Freilich B(3), Schiff E(4), Kohli A(5), Lawitz EJ(6), Hellstern PA(7), Owens-Grillo J(8), Van Biene C(8), Shringarpure R(8), MacConell L(8), Shapiro D(8), Cohen DE(9).<br />
Author information: (1)Division of Gastroenterology/Hepatology, Scripps Clinic, and the Scripps Translational Science Institute, La Jolla, CA, USA. (2)Division of Gastroenterology, Virginia Commonwealth University and Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, USA. (3)Kansas City Research Institute, Kansas City, MO, USA. (4)Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, FL, USA. (5)Institute for Liver Health, Chandler, AZ, USA. (6)Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA. (7)Nature Coast Clinical Research, Inverness, FL, USA. (8)Intercept Pharmaceuticals, San Diego, CA, USA. (9)Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA.<br />
BACKGROUND &amp; AIMS: Nonalcoholic steatohepatitis (NASH) is a chronic and severe form of nonalcoholic fatty liver disease that can progress to cirrhosis and hepatocellular carcinoma and is a risk factor for cardiovascular disease. Although NASH has no approved treatments, obeticholic acid (OCA), a synthetic bile acid and farnesoid X receptor (FXR) agonist, was shown to improve histological features of NASH and fibrosis. Considering that FXR activation influences plasma lipoprotein concentrations, the Combination OCA aNd sTatins for monitoRing Of Lipids (CONTROL) study evaluated how statins can regulate lipoprotein metabolism with OCA treatment in patients with NASH. METHODS: This randomized, double-blind, placebo-controlled, phase 2 study began with a 5-week screening/statin washout; 84 patients with NASH were randomly assigned (1:1:1:1) to receive placebo or 5&nbsp;mg, 10&nbsp;mg or 25&nbsp;mg OCA once daily during the 16-week double-blind phase. Concurrent once daily atorvastatin (10&nbsp;mg/days) was initiated at Week 4 with subsequent titration. Enrolled patients had biopsy-confirmed diagnosis of NASH with no evidence of hepatic decompensation. Plasma was collected to analyse lipoprotein parameters. RESULTS: At Week 4, all OCA groups had an increase from baseline in mean low-density lipoprotein cholesterol (LDLc) and mean LDL particle concentration (LDLpc), mostly owing to large, less atherogenic LDLc particles. Atorvastatin 10&nbsp;mg decreased LDLc and LDLpc levels below baseline in all OCA groups by Week 8; higher doses did not provide additional clinical benefits. CONCLUSIONS: The CONTROL study showed that OCA-induced increases in LDLc in patients with NASH were mitigated with atorvastatin. The combination of OCA and atorvastatin was generally safe and well tolerated (NCT02633956).<br />
DOI: 10.1111/liv.14209 PMID: 31402538 [Indexed for MEDLINE]<br />
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[3]. Biomed Pharmacother. 2017 Jan;85:372-379. doi: 10.1016/j.biopha.2016.11.038. Epub 2016 Dec 8.<br />
Effect of dietary n-3 fatty acids supplementation on fatty acid metabolism in atorvastatin-administered SHR.Cg-Lepr(cp)/NDmcr rats, a metabolic syndrome model.<br />
Al Mamun A(1), Hashimoto M(2), Katakura M(1), Tanabe Y(1), Tsuchikura S(3), Hossain S(4), Shido O(1).<br />
Author information: (1)Department of Environmental Physiology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan. (2)Department of Environmental Physiology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan. Electronic address: [email protected]. (3)Disease Model Cooperative Research Association, Hamamatsu, Shizuoka, 433-8114, Japan. (4)Department of Environmental Physiology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan; Laboratory of Alternative Medicine and Behavioral Neurosciences, Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka-1342, Bangladesh.<br />
The effects of cholesterol-lowering statins, which substantially benefit future cardiovascular events, on fatty acid metabolism have remained largely obscured. In this study, we investigated the effects of atorvastatin on fatty acid metabolism together with the effects of TAK-085 containing highly purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl ester on atorvastatin-induced n-3 polyunsaturated fatty acid lowering in SHR.Cg-Leprcp/NDmcr (SHRcp) rats, as a metabolic syndrome model. Supplementation with 10mg/kg body weight/day of atorvastatin for 17 weeks significantly decreased plasma total cholesterol and very low density lipoprotein cholesterol. Atorvastatin alone caused a subtle change in fatty acid composition particularly of EPA and DHA in the plasma, liver or erythrocyte membranes. However, the TAK-085 consistently increased both the levels of EPA and DHA in the plasma, liver and erythrocyte membranes. After confirming the reduction of plasma total cholesterol, 300mg/kg body weight/day of TAK-085 was continuously administered for another 6 weeks. Supplementation with TAK-085 did not decrease plasma total cholesterol but significantly increased the EPA and DHA levels in both the plasma and liver compared with rats administered atorvastatin only. Supplementation with atorvastatin alone significantly decreased sterol regulatory element-binding protein-1c, &Delta;5- and &Delta;6-desaturases, elongase-5, and stearoyl-coenzyme A (CoA) desaturase-2 levels and increased 3-hydroxy-3-methylglutaryl-CoA reductase mRNA expression in the liver compared with control rats. TAK-085 supplementation significantly increased stearoyl-CoA desaturase-2 mRNA expression. These results suggest that long-term supplementation with atorvastatin decreases the EPA and DHA levels by inhibiting the desaturation and elongation of n-3 fatty acid metabolism, while TAK-085 supplementation effectively replenishes this effect in SHRcp rat liver.<br />
DOI: 10.1016/j.biopha.2016.11.038 PMID: 27939244 [Indexed for MEDLINE]

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