ATORVASTATIN

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Synonyms
Status
Molecule Category Free-form
ATC C10AA05
UNII A0JWA85V8F
EPA CompTox DTXSID60274003

Structure

InChI Key XUKUURHRXDUEBC-KAYWLYCHSA-N
Smiles CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
InChI
InChI=1S/C33H35FN2O5/c1-21(2)31-30(33(41)35-25-11-7-4-8-12-25)29(22-9-5-3-6-10-22)32(23-13-15-24(34)16-14-23)36(31)18-17-26(37)19-27(38)20-28(39)40/h3-16,21,26-27,37-38H,17-20H2,1-2H3,(H,35,41)(H,39,40)/t26-,27-/m1/s1

Physicochemical Descriptors

Property Name Value
Molecular Formula C33H35FN2O5
Molecular Weight 558.65
AlogP 6.31
Hydrogen Bond Acceptor 5.0
Hydrogen Bond Donor 4.0
Number of Rotational Bond 12.0
Polar Surface Area 111.79
Molecular species ACID
Aromatic Rings 4.0
Heavy Atoms 41.0
Assay Description Organism Bioactivity Reference
Inhibitory concentration against 3-hydroxy-3-methylglutaryl-CoA reductase Homo sapiens 6.0 nM
Inhibition of HMG-CoA reductase in Sprague-Dawley rat liver microsomes Rattus norvegicus 12.0 nM
Inhibition of pig DPP4 at 500 uM Sus scrofa 66.0 %
Inhibition of rat microsomal HMGCoA reductase Rattus norvegicus 3.8 nM
Inhibition of cholesterol synthesis in rat hepatocyte Rattus norvegicus 0.99 nM
Inhibition of cholesterol synthesis in rat L6 myocyte Rattus norvegicus 142.0 nM
Inhibition of acute cholesterol synthesis in mouse at 1 mg/kg Mus musculus -75.2 %
Inhibition of HMGR in rat hepatic microsomes assessed as conversion of [14C]HMG-CoA to [14C]mevalonic acid Rattus norvegicus 6.2 nM
Inhibition of cholesterol synthesis in rat hepatocytes assessed as incorporation of [14C]acetate into cholesterol Rattus norvegicus 2.5 nM
Inhibition of cholesterol synthesis in rat L6 cells assessed as incorporation of [14C]acetate into cholesterol Rattus norvegicus 78.0 nM
DRUGMATRIX: HMG-CoA Reductase enzyme inhibition (substrate: [14C]HMG-CoA) Escherichia coli 0.227 nM
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 96.0 %
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 74.4 %
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 98.3 %
Inhibition of recombinant HMG-CoA reductase (unknown origin) after 10 mins by spectrophotometric analysis Homo sapiens 12.9 nM
Inhibition of OATP1B1 (unknown origin) expressed in HEK293 cells using pitavastatin substrate Homo sapiens 800.0 nM
Inhibition of OATP1B1 (unknown origin) expressed in HEK293 cells using estradiol-17beta-glucuronide substrate Homo sapiens 600.0 nM
Time dependent inhibition of CYP1A2 (unknown origin) at 100 uM by LC/MS system Homo sapiens 10.0 %
Time dependent inhibition of CYP2B6 (unknown origin) at 100 uM by LC/MS system Homo sapiens 10.0 %
Time dependent inhibition of CYP2C9 (unknown origin) at 100 uM by LC/MS system Homo sapiens 10.0 %
Time dependent inhibition of CYP2C19 in human liver microsomes at 100 uM by LC/MS system Homo sapiens 10.0 %
Time dependent inhibition of CYP2D6 (unknown origin) at 100 uM by LC/MS system Homo sapiens 10.0 %
Time dependent inhibition of CYP3A4 (unknown origin) at 100 uM by LC/MS system Homo sapiens 10.0 %
Time dependent inhibition of CYP2C8 (unknown origin) at 100 uM by LC/MS system Homo sapiens 10.0 %
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 7.0 nM
Reductase Activity Assay: The HMGR activity was performed using HMG-CoA reductase assay kit from Sigma-Aldrich with the human recombinant protein or 100 μg total cell lysates from A549 cells. Lovastatin was used as a positive control, and SAHA as a negative control. HMGR activity under defined assay conditions, containing NADPH and HMG-CoA substrate in a final volume of 0.2 mL of 100 mM potassium phosphatate buffer (120 mM KCl, 1 mM EDTA, 5 mM DTT, pH 7.4), were initiated in the presence or absence (control) of test compounds dissolved in dimethylsulfoxide (DMSO). The rates of NADPH consumption were monitored every 20 seconds, for up to 10 minutes, by spectrophotometer at 37° C. and 340 nm. None 11.6 nM
Inhibition of human HMG-CoA reductase catalytic domain at 10 uM using HMG-CoA as substrate in presence of NADPH by colorimetric method relative to control Homo sapiens 60.0 %
Inhibition of human HMG-CoA reductase catalytic domain at 1 uM using HMG-CoA as substrate in presence of NADPH by colorimetric method relative to control Homo sapiens 20.0 %
Inhibition of human HMG-CoA reductase catalytic domain at 5 uM using HMG-CoA as substrate in presence of NADPH by colorimetric method relative to control Homo sapiens 35.0 %
Inhibition of human HMG-CoA reductase catalytic domain at 20 uM using HMG-CoA as substrate in presence of NADPH by colorimetric method relative to control Homo sapiens 69.0 %
Inhibition of human HMG-CoA reductase catalytic domain at 50 uM using HMG-CoA as substrate in presence of NADPH by colorimetric method relative to control Homo sapiens 76.0 %
Inhibition of human HMG-CoA reductase catalytic domain at 100 uM using HMG-CoA as substrate in presence of NADPH by colorimetric method relative to control Homo sapiens 83.0 %
Antihyperlipidemic activity in triton WR-1339 induced Charles Foster rat hyperlipidemia model assessed as inhibition of total cholesterol level in serum at 10 mg/kg, po administered simultaneously with triton WR-1339 after 18 hrs by enzymatic method relative to control Rattus norvegicus 36.0 %
Antihyperlipidemic activity in triton WR-1339 induced Charles Foster rat hyperlipidemia model assessed as inhibition of phospholipid level in serum at 10 mg/kg, po administered simultaneously with triton WR-1339 after 18 hrs by enzymatic method relative to control Rattus norvegicus 35.0 %
Antihyperlipidemic activity in triton WR-1339 induced Charles Foster rat hyperlipidemia model assessed as inhibition of triglyceride level in serum at 10 mg/kg, po administered simultaneously with triton WR-1339 after 18 hrs by enzymatic method relative to control Rattus norvegicus 35.0 %
Hypolipidemic activity in HFD-induced Charles Foster rat chronic hyperlipidemia model assessed as reduction in serum total cholesterol level at 10 mg/kg administered via oral gavage for 30 days simultaneously with high fat diet by enzymatic method relative to HFD treated vehicle Rattus norvegicus 25.0 %
Hypolipidemic activity in HFD-induced Charles Foster rat chronic hyperlipidemia model assessed as reduction in serum triglyceride level at 10 mg/kg administered via oral gavage for 30 days simultaneously with high fat diet by enzymatic method relative to HFD treated vehicle Rattus norvegicus 26.0 %
Hypolipidemic activity in HFD-induced Charles Foster rat chronic hyperlipidemia model assessed as reduction in serum AST level at 10 mg/kg administered via oral gavage for 30 days simultaneously with high fat diet by colorimetric method relative to HFD treated vehicle Rattus norvegicus 29.0 %
Hypolipidemic activity in HFD-induced Charles Foster rat chronic hyperlipidemia model assessed as reduction in serum ALT level at 10 mg/kg administered via oral gavage for 30 days simultaneously with high fat diet by colorimetric method relative to HFD treated vehicle Rattus norvegicus 25.0 %
Hypolipidemic activity in HFD-induced Charles Foster rat chronic hyperlipidemia model assessed as reduction in liver total cholesterol level at 10 mg/kg administered via oral gavage for 30 days simultaneously with high fat diet by enzymatic method relative to HFD treated vehicle Rattus norvegicus 28.0 %
Hypolipidemic activity in HFD-induced Charles Foster rat chronic hyperlipidemia model assessed as reduction in liver triglyceride level at 10 mg/kg administered via oral gavage for 30 days simultaneously with high fat diet by enzymatic method relative to HFD treated vehicle Rattus norvegicus 30.0 %
Inhibition of pig liver microsomal HMG-CoA reductase by colorimetric method Sus scrofa 930.0 nM
Inhibition of HMG-CoA Reductase (unknown origin) Homo sapiens 6.2 nM

Environmental Exposure

Environmental Exposure Map
Countries
Croatia
Germany
Hungary
Romania
Slovenia

Cross References

Resources Reference
ChEBI 39548
ChEMBL CHEMBL1487
DrugBank DB01076
DrugCentral 257
FDA SRS A0JWA85V8F
Human Metabolome Database HMDB0005006
Guide to Pharmacology 2949
KEGG C06834
PDB 117
PharmGKB PA448500
PubChem 60823
SureChEMBL SCHEMBL3831
ZINC ZINC000003920719
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