Maraviroc

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C29H41F2N5O
Molecular Weight	513.6655
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)C1=NN=C(C)N1[C@H]2C[C@@H]3CC[C@H](C2)N3CC[C@H](NC(=O)C4CCC(F)(F)CC4)C5=CC=CC=C5

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
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022128s015lbl.pdf
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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
C-C chemokine receptor type 5 19 Target ID: CHEMBL274 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16298345	Antagonist 2778		0.86 nM [Kd]

Conditions

Condition	Modality	Targets	Highest Phase	Product
CCR5-tropic HIV-1 infection 1 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022128s015lbl.pdf	Primary		Approved 8429	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 2007

C_max

Value	Dose	Analyte	Population
538 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/18333861	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 DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022128s018,208984s001lbl.pdf	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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00717067	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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00717067	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

Value	Dose	Analyte	Population
2422 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/18333861	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 DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022128s018,208984s001lbl.pdf	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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00717067	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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00717067	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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00717067	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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00717067	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:

T_1/2

Value	Dose	Analyte	Population
8.63 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/18333861	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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00717067	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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00717067	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:

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:63608	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:63608
MolPort	MolPort-020-005-896	https://www.molport.com/shop/molecule-link/MolPort-020-005-896
ZINC	ZINC000100003902	http://zinc15.docking.org/substances/ZINC000100003902
eMolecules	32275895	https://www.emolecules.com/cgi-bin/more?vid=32275895

PubMed

Title	Date	PubMed
Maraviroc.	2007	17927288
First medication in new class of ARTs poised to be available for salvage therapy. Tropism testing helps determine best patients for drug.	2007 Aug	17763555
Report from the XVI International HIV Drug Resistance Workshop.	2007 Aug	17695089
Maraviroc, a chemokine CCR5 receptor antagonist for the treatment of HIV infection and AIDS.	2007 Aug	17668369
V3 loop truncations in HIV-1 envelope impart resistance to coreceptor inhibitors and enhanced sensitivity to neutralizing antibodies.	2007 Aug 24	17722977
Maraviroc (Celsentri) for multidrug-resistant human immunodeficiency virus (HIV)-1.	2007 Dec	18080399
Allosteric modulation of heterodimeric G-protein-coupled receptors.	2007 Dec	18022255
Asymmetric allylboration of acyl imines catalyzed by chiral diols.	2007 Dec 12	18020334
Species selectivity of small-molecular antagonists for the CCR5 chemokine receptor.	2007 Dec 5	17920529
Maraviroc--new HIV drug. Emerging options need to be used wisely.	2007 Jul-Aug	17682275
Maraviroc.	2007 Nov	18174962
Randomized trials to optimize treatment of multidrug-resistant tuberculosis.	2007 Nov 6	17988168
New drugs: Maraviroc and Lanreotide.	2007 Nov-Dec	18032144
Maraviroc approved in the European Union.	2007 Oct	17992719
Antiviral drugs in the treatment of AIDS: what is in the pipeline ?	2007 Oct 15	17933730
Treatment with CCR5 antagonists: which patient may have a benefit?	2007 Oct 15	17933726
How will CCR5 antagonists influence the recommendations for the antiretroviral treatment of HIV-1 infection.	2007 Oct 15	17933725
CCR5 antagonists in the treatment of treatment-naive patients infected with CCR5 tropic HIV-1.	2007 Oct 15	17933724
CCR5 antagonists in the treatment of treatment-experienced patients infected with CCR5 tropic HIV-1.	2007 Oct 15	17933723
CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions--review of the literature.	2007 Oct 15	17933722
Changes in HIV-1 tropism: clinical and prognostic consequences.	2007 Oct 15	17933716
Maraviroc reduces viral load in naive patients at 48 weeks.	2007 Sep	17941136
FDA approves maraviroc tablets.	2007 Sep	17919097
FDA approves drug for resistant HIV.	2007 Sep	17902225
Novel HIV treatment approved.	2007 Sep 15	17823091
Phylodynamics of HIV-1 in lymphoid and non-lymphoid tissues reveals a central role for the thymus in emergence of CXCR4-using quasispecies.	2007 Sep 26	17895991
Anti-HIV agents. New drugs--hope and a degree of caution.	2007 Sep-Oct	18041153
Anti-HIV agents. Using maraviroc in first-line therapy.	2007 Sep-Oct	18041149
Anti-HIV agents. Maraviroc and resistance.	2007 Sep-Oct	18041148
Anti-HIV agents. One year clinical trial results with maraviroc.	2007 Sep-Oct	18041147
Anti-HIV agents. Maraviroc approved in Canada.	2007 Sep-Oct	18041146
A receptor theory-based semimechanistic PD model for the CCR5 noncompetitive antagonist maraviroc.	2008 Apr	18333871
Population pharmacokinetic/pharmacodynamic analysis of CCR5 receptor occupancy by maraviroc in healthy subjects and HIV-positive patients.	2008 Apr	18333870
A population pharmacokinetic meta-analysis of maraviroc in healthy volunteers and asymptomatic HIV-infected subjects.	2008 Apr	18333869
Effect of single doses of maraviroc on the QT/QTc interval in healthy subjects.	2008 Apr	18333868
Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects.	2008 Apr	18333867
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	18333866
The effects of cotrimoxazole or tenofovir co-administration on the pharmacokinetics of maraviroc in healthy volunteers.	2008 Apr	18333865
Effects of CYP3A4 inducers with and without CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers.	2008 Apr	18333864
Effects of CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers.	2008 Apr	18333863
Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/zidovudine, and ethinyloestradiol/levonorgestrel in healthy volunteers.	2008 Apr	18333862
Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers.	2008 Apr	18333861
A review of the clinical pharmacology of maraviroc. Introduction.	2008 Apr	18333860
The incidence of multidrug and full class resistance in HIV-1 infected patients is decreasing over time (2001-2006) in Portugal.	2008 Feb 1	18241328
Anti-HIV-1 entry optimization of novel imidazopiperidine-tropane CCR5 antagonists.	2008 Feb 15	18194864
Post-exposure prophylaxis with a maraviroc-containing regimen after occupational exposure to a multi-resistant HIV-infected source person.	2008 Jan	18041046
Two new drugs for HIV infection.	2008 Jan 14	18197163
Variation in HIV-1 R5 macrophage-tropism correlates with sensitivity to reagents that block envelope: CD4 interactions but not with sensitivity to other entry inhibitors.	2008 Jan 18	18205925
CXCR2 chemokine receptor antagonism enhances DOP opioid receptor function via allosteric regulation of the CXCR2-DOP receptor heterodimer.	2008 Jun 1	18307412
Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists.	2008 Mar	18096812

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

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

Official Name

English

4,4-Difluoro-N-[(1S)-3-[(3-exo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl]cyclohexanecarboxamide

Systematic 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

Cyclohexanecarboxamide, 4,4-difluoro-N-[(1S)-3-[(3-exo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl]-

Systematic Name

English

CELSENTRI

Brand Name

English

UK-427,857

Code

English

SELZENTRY

Brand Name

English

MARAVIROC [MI]

Common Name

English

MARAVIROC [ORANGE BOOK]

Common Name

English

UK-427857

Code

English

Classification Tree Code System Code

LIVERTOX

NBK548266