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Details

Stereochemistry ABSOLUTE
Molecular Formula C29H41F2N5O
Molecular Weight 513.6666
Optical Activity UNSPECIFIED
Defined Stereocenters 4 / 4
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of MARAVIROC

SMILES

CC(C)c1nnc(C)n1[C@@]2([H])C[C@]3([H])CC[C@]([H])(C2)N3CC[C@@]([H])(c4ccccc4)N=C(C5CCC(CC5)(F)F)O

InChI

InChIKey=GSNHKUDZZFZSJB-QYOOZWMWSA-N
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

HIDE SMILES / InChI

Description
Curator's Comment:: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/16251317

Maraviroc (UK-427,857; brand-named Selzentry, or Celsentri outside the U.S) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Selzentry, in combination with other antiretroviral agents, is indicated for adult patients infected with only CCR5-tropic HIV-1. This indication is based on analyses of plasma HIV-1 RNA levels in two controlled trials of SELZENTRY in treatment-experienced subjects and one trial in treatment-naive subjects. Maraviroc selectively binds to the human chemokine receptor CCR5 present on the cell membrane, preventing the interaction of HIV-1 gp120 and CCR5 necessary for CCR5-tropic HIV-1 to enter cells. CXCR4-tropic and dual-tropic HIV-1 entry is not inhibited by maraviroc. Antiviral Activity in Cell Culture Maraviroc inhibits the replication of CCR5-tropic laboratory strains and primary isolates of HIV-1 in models of acute peripheral blood leukocyte infection. The mean EC50 value (50% effective concentration) for maraviroc against HIV-1 group M isolates (subtypes A to J and circulating recombinant form AE) and group O isolates ranged from 0.1 to 4.5 nM (0.05 to 2.3 ng per mL) in cell culture. When used with other antiretroviral agents in cell culture, the combination of maraviroc was not antagonistic with NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), or protease inhibitors (amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir). Maraviroc was not antagonistic with the HIV fusion inhibitor enfuvirtide. Maraviroc was not active against CXCR4-tropic and dual-tropic viruses (EC50 value greater than 10 µM). The antiviral activity of maraviroc against HIV-2 has not been evaluated. Maraviroc can cause serious, life-threatening side effects such as, liver problems, skin reactions, and allergic reactions.

CNS Activity

Curator's Comment:: Several factors suggest maraviroc may have CNS antiviral activity. First, due to pharmacological properties, such as a relatively low degree of plasma protein binding (∼76%), maraviroc may theoretically cross the blood–brain barrier (BBB) and gain exposure in the CSF at concentrations great enough to suppress HIV viral replication. Second, as a predominance of CCR5-tropic HIV has been described within the CNS, CCR5 inhibitors such as maraviroc may have profound antiviral activity within this compartment.

Originator

Curator's Comment:: from a high-throughput screen of the Pfizer compound file # Pfizer

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
0.86 nM [Kd]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
SELZENTRY

Approved Use

SELZENTRY, in combination with other antiretroviral agents, is indicated for adult patients infected with only CCR5-tropic HIV-1. This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of SELZENTRY in treatment-experienced subjects and one study in treatment-naïve subjects. Both studies in treatment-experienced subjects were conducted in clinically advanced, 3-class antiretroviral-experienced (NRTI, NNRTI, PI, or enfuvirtide) adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy. The following points should be considered when initiating therapy with SELZENTRY: Adult patients infected with only CCR5-tropic HIV-1 should use SELZENTRY. Tropism testing must be conducted with a highly sensitive tropism assay that has demonstrated the ability to identify patients appropriate for SELZENTRY use. Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on SELZENTRY. [see Microbiology (12.4) Clinical Studies (14.3)

Launch Date

1.18635836E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
538 ng/mL
300 mg 2 times / day steady-state, oral
dose: 300 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
MARAVIROC plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
888 ng/mL
300 mg 2 times / day multiple, oral
dose: 300 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
MARAVIROC plasma
Homo sapiens
population: HEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
335.6 ng/mL
300 mg single, oral
dose: 300 mg
route of administration: oral
experiment type: single
co-administered:
MARAVIROC plasma
Homo sapiens
population: healthy
age:
sex:
food status:
801.16 ng/mL
300 mg single, oral
dose: 300 mg
route of administration: oral
experiment type: single
co-administered:
MARAVIROC plasma
Homo sapiens
population: unhealthy
age:
sex:
food status:
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
2422 ng × h/mL
300 mg 2 times / day steady-state, oral
dose: 300 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
MARAVIROC plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
2908 ng × h/mL
300 mg 2 times / day multiple, oral
dose: 300 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
MARAVIROC plasma
Homo sapiens
population: HEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
1320.7 ng*h/mL
300 mg single, oral
dose: 300 mg
route of administration: oral
experiment type: single
co-administered:
MARAVIROC plasma
Homo sapiens
population: healthy
age:
sex:
food status:
4255.5 ng*h/mL
300 mg single, oral
dose: 300 mg
route of administration: oral
experiment type: single
co-administered:
MARAVIROC plasma
Homo sapiens
population: unhealthy
age:
sex:
food status:
1348.4 ng*h/mL
300 mg single, oral
dose: 300 mg
route of administration: oral
experiment type: single
co-administered:
MARAVIROC plasma
Homo sapiens
population: healthy
age:
sex:
food status:
4367.7 ng*h/mL
300 mg single, oral
dose: 300 mg
route of administration: oral
experiment type: single
co-administered:
MARAVIROC plasma
Homo sapiens
population: unhealthy
age:
sex:
food status:
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
8.63 h
300 mg 2 times / day steady-state, oral
dose: 300 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
MARAVIROC plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
14.36 h
300 mg single, oral
dose: 300 mg
route of administration: oral
experiment type: single
co-administered:
MARAVIROC plasma
Homo sapiens
population: healthy
age:
sex:
food status:
17.29 h
300 mg single, oral
dose: 300 mg
route of administration: oral
experiment type: single
co-administered:
MARAVIROC plasma
Homo sapiens
population: unhealthy
age:
sex:
food status:
PubMed

PubMed

TitleDatePubMed
Gateways to clinical trials.
2005 Jun
Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity.
2005 Nov
Human immunodeficiency virus (HIV) entry inhibitors (CCR5 specific blockers) in development: are they the next novel therapies?
2005 Sep-Oct
Erythrocyte G protein as a novel target for malarial chemotherapy.
2006 Dec
A pharmacokinetic-pharmacodynamic model to optimize the phase IIa development program of maraviroc.
2006 Jun
Gateways to clinical trials.
2006 May
Organic chemistry at the interface to biology.
2006 May
Identifying safety concerns from genetic data: lessons from the development of CCR5 inhibitors.
2007
New drugs offer options.
2007 Apr
Advances in antiretroviral therapy.
2007 Apr-May
Report from the XVI International HIV Drug Resistance Workshop.
2007 Aug
Maraviroc, a chemokine CCR5 receptor antagonist for the treatment of HIV infection and AIDS.
2007 Aug
Gateways to clinical trials.
2007 Jan-Feb
Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss.
2007 Jun
Anti-HIV agents. Maraviroc--coming soon.
2007 Mar-Apr
Anti-HIV agents. Getting to know your co-receptors.
2007 Mar-Apr
Advances in HIV therapeutics: the 14th CROI.
2007 May
Novel CCR5 monoclonal antibodies with potent and broad-spectrum anti-HIV activities.
2007 May
Antiviral drugs in the treatment of AIDS: what is in the pipeline ?
2007 Oct 15
Treatment with CCR5 antagonists: which patient may have a benefit?
2007 Oct 15
CCR5 antagonists in the treatment of treatment-experienced patients infected with CCR5 tropic HIV-1.
2007 Oct 15
CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions--review of the literature.
2007 Oct 15
Changes in HIV-1 tropism: clinical and prognostic consequences.
2007 Oct 15
FDA approves maraviroc tablets.
2007 Sep
Anti-HIV agents. One year clinical trial results with maraviroc.
2007 Sep-Oct
Anti-HIV agents. Maraviroc approved in Canada.
2007 Sep-Oct
A receptor theory-based semimechanistic PD model for the CCR5 noncompetitive antagonist maraviroc.
2008 Apr
Population pharmacokinetic/pharmacodynamic analysis of CCR5 receptor occupancy by maraviroc in healthy subjects and HIV-positive patients.
2008 Apr
A population pharmacokinetic meta-analysis of maraviroc in healthy volunteers and asymptomatic HIV-infected subjects.
2008 Apr
Effect of single doses of maraviroc on the QT/QTc interval in healthy subjects.
2008 Apr
Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects.
2008 Apr
A novel probe drug interaction study to investigate the effect of selected antiretroviral combinations on the pharmacokinetics of a single oral dose of maraviroc in HIV-positive subjects.
2008 Apr
The effects of cotrimoxazole or tenofovir co-administration on the pharmacokinetics of maraviroc in healthy volunteers.
2008 Apr
Effects of CYP3A4 inducers with and without CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers.
2008 Apr
Effects of CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers.
2008 Apr
Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/zidovudine, and ethinyloestradiol/levonorgestrel in healthy volunteers.
2008 Apr
Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers.
2008 Apr
A review of the clinical pharmacology of maraviroc. Introduction.
2008 Apr
Anti-HIV-1 entry optimization of novel imidazopiperidine-tropane CCR5 antagonists.
2008 Feb 15
Patents

Sample Use Guides

The recommended dose of SELZENTRY (maraviroc tablets, for oral use) differs based on concomitant medications due to drug interactions. SELZENTRY can be taken with or without food. SELZENTRY must be given in combination with other antiretroviral medications.
Route of Administration: Oral
PM-1 cells were infected with CCR5-tropic HIV-1 BaL in the presence or absence of inhibitory concentrations of maraviroc (MVC) 50 nM or controls. P24 and viral load levels were measured by ELISA and qRT-PCR after 4 hours.
Name Type Language
MARAVIROC
EMA EPAR   INN   JAN   MART.   MI   ORANGE BOOK   VANDF   WHO-DD  
INN  
Official Name English
4,4-DIFLUORO-N-((1S)-3-((1R,3S,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)CYCLOHEXANECARBOXAMIDE
Common Name English
MARAVIROC [INN]
Common Name English
MARAVIROC [EMA EPAR]
Common Name English
MARAVIROC [VANDF]
Common Name English
MARAVIROC [MART.]
Common Name English
MARAVIROC [JAN]
Common Name English
MARAVIROC [WHO-DD]
Common Name English
CELSENTRI
Brand Name English
SELZENTRY
Brand Name English
MARAVIROC [MI]
Common Name English
MARAVIROC [ORANGE BOOK]
Common Name English
Classification Tree Code System Code
LIVERTOX 582
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
NDF-RT N0000175572
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
WHO-VATC QJ05AX09
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
NCI_THESAURUS C1660
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
NCI_THESAURUS C63817
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
EMA ASSESSMENT REPORTS CELSENTRI (AUTHORIZED: HIV INFECTIONS)
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
WHO-ATC J05AX09
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
NDF-RT N0000175445
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
Code System Code Type Description
MESH
C502411
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY
HSDB
8021
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY
EPA CompTox
376348-65-1
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY
DRUG CENTRAL
1635
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY
IUPHAR
806
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY
INN
8450
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY
EVMPD
SUB25224
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY
CAS
376348-65-1
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY
NCI_THESAURUS
C73144
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY
FDA UNII
MD6P741W8A
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY
MERCK INDEX
M7084
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY Merck Index
ChEMBL
CHEMBL1201187
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY
RXCUI
620216
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY RxNorm
WIKIPEDIA
MARAVIROC
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY
LACTMED
Maraviroc
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY
DRUG BANK
DB04835
Created by admin on Sat Jun 26 12:28:53 UTC 2021 , Edited by admin on Sat Jun 26 12:28:53 UTC 2021
PRIMARY