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Identification
NameSIMEPREVIR
Accession NumberDB06290
TypeSmall Molecule
GroupsApproved
Description

Simeprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated in patient’s with HCV genotype 1 for the treatment of chronic hepatitis as a combination therapy, which includes peginterferon alfa and ribavirin. It was approved by the FDA in November 2014 and is marketed under the brand name Olysio.

Structure
Thumb
Synonyms
SynonymLanguageCode
TMC435EnglishInvestigational name
TMC435350EnglishInvestigational name
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Olysiocapsule150 mgoralJanssen Products LP2013-11-22Not AvailableUs
Galexoscapsule150 mgoralJanssen IncNot AvailableNot AvailableCanada
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number923604-59-5
WeightAverage: 749.939
Monoisotopic: 749.291690263
Chemical FormulaC38H47N5O7S2
InChI KeyJTZZSQYMACOLNN-RCSAWCOCNA-N
InChI
InChI=1/C38H47N5O7S2/c1-21(2)30-20-51-35(40-30)29-18-32(26-13-14-31(49-5)22(3)33(26)39-29)50-24-16-27-28(17-24)36(45)43(4)15-9-7-6-8-10-23-19-38(23,41-34(27)44)37(46)42-52(47,48)25-11-12-25/h8,10,13-14,18,20-21,23-25,27-28H,6-7,9,11-12,15-17,19H2,1-5H3,(H,41,44)(H,42,46)/b10-8-/t23-,24?,27+,28+,38+/s2
IUPAC Name
(1R,4R,6R,7Z,15R)-N-(cyclopropanesulfonyl)-17-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0⁴,⁶]octadec-7-ene-4-carboxamide
SMILES
[H][C@]12C[C@]1(NC(=O)[C@]1([H])CC(C[C@@]1([H])C(=O)N(C)CCCC\C=C/2)OC1=CC(=NC2=C(C)C(OC)=CC=C12)C1=NC(=CS1)C(C)C)C(=O)NS(=O)(=O)C1CC1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as macrolactams. These are cyclic amides of amino carboxylic acids, having a 1-azacycloalkan-2-one structure, or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. They are nitrogen analogues (the a nitrogen atom replacing the o atom of the cyclic carboxylic acid group ) of the naturally occurring macrolides.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassMacrolactams
Sub ClassNot Available
Direct ParentMacrolactams
Alternative Parents
Substituents
  • Macrolactam
  • Alpha-amino acid amide
  • Quinoline
  • Anisole
  • Alkyl aryl ether
  • 2,4-disubstituted 1,3-thiazole
  • Benzenoid
  • Pyridine
  • Cyclopropanecarboxylic acid or derivatives
  • Heteroaromatic compound
  • Aminosulfonyl compound
  • Thiazole
  • Tertiary carboxylic acid amide
  • Sulfonyl
  • Sulfonic acid derivative
  • Sulfonamide
  • Azole
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Lactam
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Ether
  • Carboxylic acid derivative
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationSimeprevir is indicated in patient's with hepatitis C virus (HCV) genotype 1 for the treatment of chronic hepatitis as a combination therapy, which includes peginterferon alfa and ribavirin.
PharmacodynamicsSimeprevir is a protease inhibitor for HCV NS3/4A protease, which is required for replication of the virus.
Mechanism of actionSimeprevir functions as a direct-acting antiviral agent because it inhibits hepatitis C viral replication by binding to and inhibiting the protease, hepatitis C virus (HCV) NS3/4A.
AbsorptionAfter oral administration, simeprevir reaches its maximum plasma concentrations in 4-6 hours.
Volume of distribution

The volume of distribution for simeprevir has yet to be determined.

Protein bindingSimeprevir is >99.9% plasma protein bound with albumin being the main plasma protein.
Metabolism

Simeprevir is mainly metabolized by CYP3A enzymes.

Route of eliminationSimeprevir is mainly eliminated through biliary excretion (91%). Elimination through the urine is insignificant (1%).
Half lifeThe half-life of simeprevir is about 41 hours in HCV patients.
Clearance

The clearance of simeprevir has yet to be determined.

ToxicityIn patients receiving the combination therapy, the most common adverse reactions were nausea, pruritus, photosensitivity, and rash.
Affected organisms
  • Hepatitis C virus, RSV and other RNA/DNA viruses
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal AbsorptionNot AvailableNot Available
Blood Brain BarrierNot AvailableNot Available
Caco-2 permeableNot AvailableNot Available
P-glycoprotein substrateNot AvailableNot Available
P-glycoprotein inhibitor INot AvailableNot Available
P-glycoprotein inhibitor IINot AvailableNot Available
Renal organic cation transporterNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 1A2 substrateNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 2C19 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 inhibitory promiscuityNot AvailableNot Available
Ames testNot AvailableNot Available
CarcinogenicityNot AvailableNot Available
BiodegradationNot AvailableNot Available
Rat acute toxicityNot AvailableNot applicable
hERG inhibition (predictor I)Not AvailableNot Available
hERG inhibition (predictor II)Not AvailableNot Available
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Capsuleoral150 mg
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00303 mg/mLALOGPS
logP4.69ALOGPS
logP4.56ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)3.77ChemAxon
pKa (Strongest Basic)1.62ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area156.89 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity206.95 m3·mol-1ChemAxon
Polarizability79.98 Å3ChemAxon
Number of Rings7ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Raboisson P, de Kock H, Rosenquist A, Nilsson M, Salvador-Oden L, Lin TI, Roue N, Ivanov V, Wahling H, Wickstrom K, Hamelink E, Edlund M, Vrang L, Vendeville S, Van de Vreken W, McGowan D, Tahri A, Hu L, Boutton C, Lenz O, Delouvroy F, Pille G, Surleraux D, Wigerinck P, Samuelsson B, Simmen K: Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350. Bioorg Med Chem Lett. 2008 Sep 1;18(17):4853-8. doi: 10.1016/j.bmcl.2008.07.088. Epub 2008 Jul 24.

General Reference
  1. Raboisson P, de Kock H, Rosenquist A, Nilsson M, Salvador-Oden L, Lin TI, Roue N, Ivanov V, Wahling H, Wickstrom K, Hamelink E, Edlund M, Vrang L, Vendeville S, Van de Vreken W, McGowan D, Tahri A, Hu L, Boutton C, Lenz O, Delouvroy F, Pille G, Surleraux D, Wigerinck P, Samuelsson B, Simmen K: Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350. Bioorg Med Chem Lett. 2008 Sep 1;18(17):4853-8. doi: 10.1016/j.bmcl.2008.07.088. Epub 2008 Jul 24. Pubmed
  2. FDA label.
External Links
ATC CodesJ05AE14
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (85.3 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. NS3 protease

Kind: protein

Organism: Hepatitis C virus

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
NS3 protease Q91RS4 Details

References:

  1. FDA label.
  2. Raboisson P, de Kock H, Rosenquist A, Nilsson M, Salvador-Oden L, Lin TI, Roue N, Ivanov V, Wahling H, Wickstrom K, Hamelink E, Edlund M, Vrang L, Vendeville S, Van de Vreken W, McGowan D, Tahri A, Hu L, Boutton C, Lenz O, Delouvroy F, Pille G, Surleraux D, Wigerinck P, Samuelsson B, Simmen K: Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350. Bioorg Med Chem Lett. 2008 Sep 1;18(17):4853-8. doi: 10.1016/j.bmcl.2008.07.088. Epub 2008 Jul 24. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: no

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. FDA label.
  2. Lexicomp

2. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: no

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Lexicomp

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: no

Actions: binder

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. FDA label.

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: no

Actions: substrate inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. FDA label.
  2. Lexicomp.

2. Solute carrier organic anion transporter family member 1B1

Kind: protein

Organism: Human

Pharmacological action: no

Actions: substrate inhibitor

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1B1 Q9Y6L6 Details

References:

  1. FDA label.
  2. Lexicomp.

Comments
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Drug created on March 19, 2008 10:22 / Updated on January 01, 2014 21:24