ROSUVASTATIN

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Synonyms
Status
Molecule Category Free-form
ATC C10AA07
UNII 413KH5ZJ73
EPA CompTox DTXSID8048492

Structure

InChI Key BPRHUIZQVSMCRT-VEUZHWNKSA-N
Smiles CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
InChI
InChI=1S/C22H28FN3O6S/c1-13(2)20-18(10-9-16(27)11-17(28)12-19(29)30)21(14-5-7-15(23)8-6-14)25-22(24-20)26(3)33(4,31)32/h5-10,13,16-17,27-28H,11-12H2,1-4H3,(H,29,30)/b10-9+/t16-,17-/m1/s1

Physicochemical Descriptors

Property Name Value
Molecular Formula C22H28FN3O6S
Molecular Weight 481.55
AlogP 2.4
Hydrogen Bond Acceptor 7.0
Hydrogen Bond Donor 3.0
Number of Rotational Bond 10.0
Polar Surface Area 140.92
Molecular species ACID
Aromatic Rings 2.0
Heavy Atoms 33.0
Assay Description Organism Bioactivity Reference
Inhibitory constant against HMG-CoA reductase Homo sapiens 0.9 nM
Inhibitory concentration against HMG-CoA reductase Homo sapiens 5.4 nM
Inhibitory concentration against 3-hydroxy-3-methylglutaryl-CoA reductase Homo sapiens 5.0 nM
Inhibition of rat microsomal HMG-CoA reductase assessed as inhibition of cholesterol synthesis after 30 mins Rattus norvegicus 3.6 nM
Inhibition of cholesterol synthesis in rat liver hepatocytes after 4 hrs Rattus norvegicus 0.23 nM
Inhibition of cholesterol synthesis in rat L6 cells after 3 hrs Rattus norvegicus 720.0 nM
Inhibition of cholesterol synthesis in C57/BL6 mouse at 10 mg/kg, po by MAICS assay Mus musculus -82.0 %
Inhibition of HMG-CoA reductase None 3.1 nM
Inhibition of cholesterol synthesis in rat hepatocyte Rattus norvegicus 0.27 nM
Inhibition of cholesterol synthesis in rat myocyte Rattus norvegicus 250.0 nM
Inhibition of acute cholesterol synthesis in mouse at 1 mg/kg Mus musculus -82.0 %
Inhibition of HMG-CoA reductase in rat liver microsomes Rattus norvegicus 2.1 nM
Inhibition of cholesterol synthesis in rat hepatocytes Rattus norvegicus 0.23 nM
Inhibition of cholesterol synthesis in L6 myocytes Rattus norvegicus 210.0 nM
Inhibition of HMG-CoA reductase in Sprague-Dawley rat liver microsomes Rattus norvegicus 3.1 nM
Inhibition of cholesterol synthesis in rat hepatocytes Rattus norvegicus 0.3 nM
Inhibition of cholesterol synthesis in rat L6 cells Rattus norvegicus 250.0 nM
Inhibition of cholesterol synthesis in Goldern Syrian hamster blood at 10 mg/kg, po after 2 to 4 hrs relative to control Mesocricetus auratus -76.0 %
Inhibition of cholesterol synthesis in Golden Syrian hamster blood at 10 mg/kg, po after 4 to 6 hrs relative to control Mesocricetus auratus -46.0 %
Inhibition of pig DPP4 at 500 uM Sus scrofa 4.0 %
Inhibition of rat microsomal HMGCoA reductase Rattus norvegicus 3.7 nM
Inhibition of cholesterol synthesis in rat hepatocyte Rattus norvegicus 0.27 nM
Inhibition of cholesterol synthesis in rat L6 myocyte Rattus norvegicus 250.0 nM
Inhibition of acute cholesterol synthesis in mouse at 1 mg/kg Mus musculus -82.4 %
Reduction of LDL cholesterol level in syrian golden hamster plasma Mesocricetus auratus -62.0 %
Binding affinity to HMG-CoA reductase by isothermal calorimetry None 17.0 nM
Inhibition of cholesterol synthesis in rat liver microsomes Rattus norvegicus 3.6 nM
Inhibition of cholesterol synthesis in rat hepatocytes Rattus norvegicus 0.23 nM
Inhibition of cholesterol synthesis in rat L6 myocytes Rattus norvegicus 720.0 nM
Acute inhibition of cholesterol synthesis in mouse at 30 mg/kg Mus musculus -82.0 %
Inhibition of HMGR in rat hepatic microsomes assessed as conversion of [14C]HMG-CoA to [14C]mevalonic acid Rattus norvegicus 3.1 nM
Inhibition of cholesterol synthesis in rat hepatocytes assessed as incorporation of [14C]acetate into cholesterol Rattus norvegicus 0.6 nM
Inhibition of cholesterol synthesis in rat L6 cells assessed as incorporation of [14C]acetate into cholesterol Rattus norvegicus 65.0 nM
Inhibition of HMG-CoA reductase in Sprague-Dawley rat liver microsomes using [14C]HMG-CoA as substrate preincubated for 0.5 hrs before substrate addition measured after 0.75 hrs by beta scintillation counting Rattus norvegicus 3.1 nM
Inhibition of cholesterol synthesis in rat hepatocytes assessed as reduction of [14C]-cholesterol level using [14C]-acetic acid preincubated for 4 hrs before addition of [14C]-acetic acid by liquid scintillation counting Rattus norvegicus 0.3 nM
Inhibition of cholesterol synthesis in rat L6 cells assessed as reduction of [14C]-cholesterol level using [14C]-acetic acid preincubated for 3 hrs before addition of [14C]-acetic acid by scintillation counting Rattus norvegicus 250.0 nM
Inhibition of cholesterol synthesis in golden syrian hamster assessed as reduction of [14C]-cholesterol level at 10 mg/kg, po followed by 2 hrs after treated with 80 uCi, ip of [14C]-sodium acetate measured after 4 hrs by liquid scintillation counting relative to control Mesocricetus auratus -76.0 %
Inhibition of HMG-CoA reductase in human assessed as decrease in AUC (0 to 24 hrs) of mevalonate level in plasma at 10 mg administered qd for 14 days relative to control Homo sapiens 29.9 %
Inhibition of HMG-CoA reductase in human assessed as decrease in LDL-cholesterol level in plasma at 10 mg administered qd for 14 days relative to control Homo sapiens 41.3 %
Drug uptake in rat hepatocytes in presence of pan OATP inhibitor rifamycin Rattus norvegicus 96.0 %
Drug uptake in human hepatocytes in presence of pan OATP inhibitor rifamycin Homo sapiens 81.0 %
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting Homo sapiens 71.4 %
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting Homo sapiens 55.4 %
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting Homo sapiens 51.2 %
Reductase Assay : The following procedure was followed using a HMG-CoA Reductase assay kit obtained from Sigma-Aldrich (catalogue number CS1090). The assay is based on the spectrophotometric measurement of the decrease in absorbance at 340 nm of NADPH in solution. A decrease in absorbance is caused by the oxidation of NADPH by the catalytic subunit of HMGR in the presence of the substrate HMG-CoA. Effective inhibition of the HMG-CoA leads to a reduction in oxidation of NADPH which in turn leads to a smaller reduction in the absorbance at 340 nm over time. None 4.0 nM
Reductase Assay: All assays were carried out in a reaction buffer containing 100 nM KxPO4 at pH 7.2, 1 mM EDTA, 500 mM KCl and 1 mg/ml BSA. The concentrations of NADPH and HMG-CoA were both 200 μM. The enzyme concentration used is unknown although this concentration is 10-fold lower than that of the stock solution purchased. Inhibitors were dissolved in 75% DMSO. Where inhibitors were found to be insoluble or only partly soluble in 75% DMSO, 100% DMSO was used. Reactions were activated by the addition of enzyme and agitated for 12 seconds following the addition. Absorbance readings were then taken every 20 seconds for 600 seconds. In initial tests the concentration of each inhibitor was set at 50 nM to identify which compounds were the better inhibitors, compared to the known Pravastatin inhibitor. Rattus norvegicus 4.0 nM

Cross References

Resources Reference
ChEBI 38545
ChEMBL CHEMBL1496
DrugBank DB01098
DrugCentral 2406
FDA SRS 413KH5ZJ73
Human Metabolome Database HMDB0015230
Guide to Pharmacology 2954
PubChem 446157
SureChEMBL SCHEMBL2520
ZINC ZINC000001535101
CONTENTS