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Identification
NameMaraviroc
Accession NumberDB04835
TypeSmall Molecule
GroupsApproved, Investigational
Description

Maraviroc (brand-named Selzentry, or Celsentri outside the U.S.) is a chemokine receptor antagonist drug developed by the drug company Pfizer that is designed to act against HIV by interfering with the interaction between HIV and CCR5. It was originally labelled as UK-427857 during development but was assigned the Maraviroc name as it entered trials. It was approved for use by the FDA in August, 2007.

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
CelsentriNot Available
SelzentryNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number376348-65-1
WeightAverage: 513.6655
Monoisotopic: 513.327917369
Chemical FormulaC29H41F2N5O
InChI KeyGSNHKUDZZFZSJB-HLMSNRGBSA-N
InChI
InChI=1S/C29H41F2N5O/c1-19(2)27-34-33-20(3)36(27)25-17-23-9-10-24(18-25)35(23)16-13-26(21-7-5-4-6-8-21)32-28(37)22-11-14-29(30,31)15-12-22/h4-8,19,22-26H,9-18H2,1-3H3,(H,32,37)/t23-,24+,25?,26-/m0/s1
IUPAC Name
4,4-difluoro-N-[(1S)-3-[(1R,5S)-3-[3-methyl-5-(propan-2-yl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl]cyclohexane-1-carboxamide
SMILES
[H][C@]12CC[C@]([H])(CC(C1)N1C(C)=NN=C1C(C)C)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)C1=CC=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenylpropylamines
Direct parentPhenylpropylamines
Alternative parentsTropanes; Aminopiperidines; Triazoles; Pyrrolidines; Secondary Carboxylic Acid Amides; Tertiary Amines; Polyamines; Enolates; Carboxylic Acids; Organofluorides; Alkyl Fluorides
Substituents4-aminopiperidine; piperidine; azole; 1,2,4-triazole; pyrrolidine; tertiary amine; carboxamide group; secondary carboxylic acid amide; carboxylic acid derivative; polyamine; enolate; carboxylic acid; organofluoride; organohalogen; amine; alkyl halide; alkyl fluoride; organonitrogen compound
Classification descriptionThis compound belongs to the phenylpropylamines. These are compounds containing a phenylpropylamine moiety, which consists of a phenyl group substituted at the third carbon by an propan-1-amine.
Pharmacology
IndicationFor treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable, who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.
PharmacodynamicsMaraviroc is a chemokine receptor antagonist drug developed by the drug company Pfizer that is designed to act against HIV by interfering with the interaction between HIV and CCR5.
Mechanism of actionMaraviroc is an entry inhibitor and works by blocking HIV from entering human cells. Specifically maraviroc is a selective, slowly reversible, small molecule antagonist of the interaction between human CCR5 and HIV-1 gp120. Maraviroc selectively binds to the human chemokine receptor CCR5 present on the membrane of CD4 cells (T-cells), preventing the interaction of HIV-1 gp120 and CCR5 necessary for CCR5-tropic HIV-1 to enter cells.
AbsorptionThe absolute oral bioavailability of a 100 mg dose is 23% and is predicted to be 33% at 300 mg. Coadministration of a 300mg tablet with a high fat breakfast reduced maraviroc Cmax and AUC by 33% in healthy volunteers.
Volume of distribution
  • 194 L
Protein bindingApproximately 76% bound to human plasma proteins, with moderate affinity for albumin and alpha-1 acid glycoprotein.
Metabolism

In vitro studies indicate that CYP3A is the major enzyme responsible for maraviroc metabolism.

Route of eliminationNot Available
Half life14-18 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Human Immunodeficiency Virus
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.997
Blood Brain Barrier + 0.8329
Caco-2 permeable - 0.8957
P-glycoprotein substrate Substrate 0.6716
P-glycoprotein inhibitor I Inhibitor 0.8931
P-glycoprotein inhibitor II Inhibitor 0.9431
Renal organic cation transporter Non-inhibitor 0.5695
CYP450 2C9 substrate Non-substrate 0.8308
CYP450 2D6 substrate Non-substrate 0.7344
CYP450 3A4 substrate Substrate 0.8199
CYP450 1A2 substrate Non-inhibitor 0.8616
CYP450 2C9 substrate Inhibitor 0.6028
CYP450 2D6 substrate Non-inhibitor 0.8331
CYP450 2C19 substrate Inhibitor 0.5684
CYP450 3A4 substrate Inhibitor 0.6066
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7814
Ames test Non AMES toxic 0.63
Carcinogenicity Non-carcinogens 0.706
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.7115 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9864
hERG inhibition (predictor II) Inhibitor 0.8971
Pharmacoeconomics
Manufacturers
  • Viiv healthcare co
Packagers
Dosage forms
FormRouteStrength
Tablet, film coatedOral
Prices
Unit descriptionCostUnit
Selzentry 150 mg tablet18.36USDtablet
Selzentry 300 mg tablet18.36USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States73684602002-11-252022-11-25
United States65864301999-12-012019-12-01
Canada23500732007-04-172019-12-23
Canada24089092006-06-272021-05-09
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0106ALOGPS
logP4.3ALOGPS
logP3.63ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)14.5ChemAxon
pKa (Strongest Basic)9.38ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area63.05 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity142.88 m3·mol-1ChemAxon
Polarizability55.59 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US020013337
General ReferenceNot Available
External Links
ResourceLink
PubChem Compound3002977
PubChem Substance46508040
ChemSpider2273675
Therapeutic Targets DatabaseDNC001487
PharmGKBPA164768835
IUPHAR806
Guide to Pharmacology806
RxListhttp://www.rxlist.com/cgi/generic/selzentry.htm
Drugs.comhttp://www.drugs.com/cdi/maraviroc.html
WikipediaMaraviroc
ATC CodesJ05AX09
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(241 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
Azilsartan medoxomilPharmacodynamic synergist- increases effects.
ConivaptanCYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. When used with a strong CYP3A4 inhibitor, the adult dose of maraviroc should be decreased to 150 mg twice daily. Maraviroc is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min) receiving a strong CYP3A4 inhibitor. Maraviroc may be administered at a dose of 300 mg twice daily with concomitant tipranavir/ritonavir but not with other ritonavir combinations.
EtravirineMaraviroc, when used concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration. It is recommended to avoid concurrent therapy.
TelithromycinTelithromycin may reduce clearance of Maraviroc. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Maraviroc if Telithromycin is initiated, discontinued or dose changed.
TopiramateTopiramate, a CYP3A4 inducer, may decrease the serum concentration of Maraviroc by increasing Maraviroc metabolism and clearance. A dose adjustment of Maraviroc may be required. Monitor for changes in Maraviroc therapeutic and adverse effects if Topiramate is initiated, discontinued or dose changed.
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of maraviroc by decreasing its metabolism. A dose reduction in maraviroc is warranted. Monitor for changes in the therapeutic and adverse effects of maraviroc if voriconazole is initiated, discontinued or dose changed.
Food InteractionsNot Available

Targets

1. C-C chemokine receptor type 5

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
C-C chemokine receptor type 5 P51681 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  4. Levy JA: HIV pathogenesis: 25 years of progress and persistent challenges. AIDS. 2009 Jan 14;23(2):147-60. Pubmed
  5. Agrawal-Gamse C, Lee FH, Haggarty B, Jordan AP, Yi Y, Lee B, Collman RG, Hoxie JA, Doms RW, Laakso MM: Adaptive mutations in a human immunodeficiency virus type 1 envelope protein with a truncated V3 loop restore function by improving interactions with CD4. J Virol. 2009 Nov;83(21):11005-15. Epub 2009 Aug 19. Pubmed
  6. Napier C, Sale H, Mosley M, Rickett G, Dorr P, Mansfield R, Holbrook M: Molecular cloning and radioligand binding characterization of the chemokine receptor CCR5 from rhesus macaque and human. Biochem Pharmacol. 2005 Dec 19;71(1-2):163-72. Epub 2005 Nov 18. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Abel S, Back DJ, Vourvahis M: Maraviroc: pharmacokinetics and drug interactions. Antivir Ther. 2009;14(5):607-18. Pubmed
  2. Abel S, Jenkins TM, Whitlock LA, Ridgway CE, Muirhead GJ: Effects of CYP3A4 inducers with and without CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers. Br J Clin Pharmacol. 2008 Apr;65 Suppl 1:38-46. Pubmed
  3. Mannu J, Jenardhanan P, Mathur PP: A computational study of CYP3A4 mediated drug interaction profiles for anti-HIV drugs. J Mol Model. 2010 Nov 16. Pubmed

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Drug created on September 11, 2007 19:14 / Updated on October 08, 2013 14:24