ETRAVIRINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C20H15BrN6O
Molecular Weight	435.277
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cc1cc(cc(C)c1Oc2c(c(N)nc(Nc3ccc(cc3)C#N)n2)Br)C#N

InChI

InChIKey=PYGWGZALEOIKDF-UHFFFAOYSA-N

InChI=1S/C20H15BrN6O/c1-11-7-14(10-23)8-12(2)17(11)28-19-16(21)18(24)26-20(27-19)25-15-5-3-13(9-22)4-6-15/h3-8H,1-2H3,(H3,24,25,26,27)

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022187lbl.pdf
Curator's Comment:: description was created based on several sources, including: https://www.drugs.com/ppa/etravirine.html | http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000900/WC500034183.pdf | http://www.wikidoc.org/index.php/Etravirine

Etravirine (formerly known as TMC125) is an antiretroviral agent more specifically classified as a Non-Nucleoside Reverse Transcriptase Inhibitor. Etravirine exerts its effects via direct inhibition of the reverse transcriptase enzyme of human immunodeficiency virus type 1 (HIV-1). It directly binds reverse transcriptase and consequently blocks DNA-dependent and RNA-dependent polymerase activity. In combination with other antiretroviral agents, it is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents. The most common adverse events (incidence > 10%) of any intensity that occurred at a higher rate than placebo are rash and nausea. Etravirine should not be co-administered with the following antiretrovirals: Tipranavir/ritonavir, fosamprenavir/ritonavir, atazanavir/ritonavir; Protease inhibitors administered without ritonavir; NNRTIs.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
P-glycoprotein 1 49 Target ID: CHEMBL4302 Sources: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000900/WC500034183.pdf	Inhibitor 7709		24.2 µM [IC50]
Human immunodeficiency virus type 1 reverse transcriptase 45 Target ID: CHEMBL247 Sources: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000900/WC500034183.pdf	Inhibitor 7709		38.4 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
HIV-1 infection 140 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022187lbl.pdf	Primary		Approved 8003	INTELENCE Approved Use INTELENCE® Registered trademark of Tibotec Pharmaceuticals, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents. This indication is based on Week 48 analyses from 2 randomized, double-blind, placebo-controlled trials of INTELENCE®. Both studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, N[t Launch Date 1.20061441E12

C_max

Value	Dose	Co-administered	Analyte	Population
296.74 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022187lbl.pdf	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered: DARUNAVIR	DARUNAVIR	ETRAVIRINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED

AUC

Value	Dose	Co-administered	Analyte	Population
4531.53 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022187lbl.pdf	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered: DARUNAVIR	DARUNAVIR	ETRAVIRINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED

T_1/2

Value	Dose	Co-administered	Analyte	Population
41 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022187lbl.pdf	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered: DARUNAVIR	DARUNAVIR	ETRAVIRINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022187lbl.pdf	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered: DARUNAVIR	DARUNAVIR	ETRAVIRINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED

Doses

Dose	Population	Adverse events
800 mg 2 times / day multiple, oral Highest studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17413684 Page: F6	unhealthy, 29–63 n = 79 Health Status: unhealthy Condition: HIV-1 infection Age Group: 29–63 Sex: M+F Population Size: 79 Sources: https://pubmed.ncbi.nlm.nih.gov/17413684 Page: F6	Sources: https://pubmed.ncbi.nlm.nih.gov/17413684 Page: F6
200 mg 2 times / day multiple, oral Recommended Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.5	unhealthy n = 599 Health Status: unhealthy Condition: HIV-1 infection Population Size: 599 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.5	Disc. AE: Rash... AEs leading to discontinuation/dose reduction: Rash (2.2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.5
200 mg 2 times / day multiple, oral Recommended Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.1	Disc. AE: Reaction skin, Stevens-Johnson syndrome... AEs leading to discontinuation/dose reduction: Reaction skin (severe\|grade 4\|grade 5) Stevens-Johnson syndrome (severe\|grade 4\|grade 5) Hypersensitivity reaction (severe\|grade 4\|grade 5) Toxic epidermal necrolysis (severe\|grade 4\|grade 5) Erythema multiforme (severe\|grade 4\|grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.1

AEs

AE	Significance	Dose	Population
Rash	2.2% Disc. AE	200 mg 2 times / day multiple, oral Recommended Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.5	unhealthy n = 599 Health Status: unhealthy Condition: HIV-1 infection Population Size: 599 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.5
Erythema multiforme	severe\|grade 4\|grade 5 Disc. AE	200 mg 2 times / day multiple, oral Recommended Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.1
Hypersensitivity reaction	severe\|grade 4\|grade 5 Disc. AE	200 mg 2 times / day multiple, oral Recommended Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.1
Reaction skin	severe\|grade 4\|grade 5 Disc. AE	200 mg 2 times / day multiple, oral Recommended Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.1
Stevens-Johnson syndrome	severe\|grade 4\|grade 5 Disc. AE	200 mg 2 times / day multiple, oral Recommended Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.1
Toxic epidermal necrolysis	severe\|grade 4\|grade 5 Disc. AE	200 mg 2 times / day multiple, oral Recommended Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022187s009lbl.pdf Page: p.1

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:63589	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:63589
ChemicalBook	CB51509336	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB51509336
MolPort	MolPort-009-194-145	https://www.molport.com/shop/molecule-link/MolPort-009-194-145
Selleck Chemicals	etravirine-tmc125	http://www.selleckchem.com/products/etravirine-tmc125.html
ZINC	ZINC000000602632	http://zinc15.docking.org/substances/ZINC000000602632
eMolecules	31592739	https://www.emolecules.com/cgi-bin/more?vid=31592739

PubMed

Title	Date	PubMed
Correlations between factors determining the pharmacokinetics and antiviral activity of HIV-1 non-nucleoside reverse transcriptase inhibitors of the diaryltriazine and diarylpyrimidine classes of compounds.	2004	15357624
Recent advances in the development of next generation non-nucleoside reverse transcriptase inhibitors.	2004	15193138
TMC125: important one-year trial now recruiting in U.S.	2004 Apr 30	15199848
Effect of stereo and regiochemistry towards wild and multidrug resistant HIV-1 virus: viral potency of chiral PETT derivatives.	2004 May 15	15130770
Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants.	2004 May 6	15115397
A series of diaryltriazines and diarylpyrimidines are highly potent nonnucleoside reverse transcriptase inhibitors with possible applications as microbicides.	2004 Oct	15388420
New non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development for the treatment of HIV infections.	2004 Oct	15351347
HIV-chemotherapy and -prophylaxis: new drugs, leads and approaches.	2004 Sep	15183346
New drugs.	2005 Jul	16011526
Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors.	2005 Jun	15572156
Emerging anti-HIV drugs.	2005 May	15934866
The molecular basis of resilience to the effect of the Lys103Asn mutation in non-nucleoside HIV-1 reverse transcriptase inhibitors studied by targeted molecular dynamics simulations.	2005 May 25	15898808
TMC125: new results, large phase III trial begins.	2005 Oct-Nov	16388542
Report from the 13th retrovirus conference. New data on TMC114 and TMC125.	2006 Apr	16718876
Optimization of diarylamines as non-nucleoside inhibitors of HIV-1 reverse transcriptase.	2006 Feb	16298131
The clinical pharmacology of antiretrovirals in development.	2006 Jun	16863445
British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2006).	2006 Nov	17105508
Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers.	2007	17713162
Antiretroviral treatment of HIV infection: Swedish recommendations 2007.	2007	17577810
Prevalence of etravirine (TMC-125) resistance mutations in HIV-infected patients with prior experience of non-nucleoside reverse transcriptase inhibitors.	2007 Dec	17913723
TMC125 (etravirine), a second generation non-nucleoside reverse transcriptase inhibitor.	2007 Feb	17763547
Expanded drug access: etravirine (formerly TMC-125).	2007 Jan	17569170
Anti-HIV agents. Brain side effects not common with etravirine.	2007 Jan	17393565
Anti-HIV agents. Effectiveness of etravirine in treatment-experienced PHAs.	2007 Jan	17393564
Anti-HIV agents. Etravirine--interactions with some medications.	2007 Jan	17390478
Anti-HIV agents. The need for etravirine (TMC125).	2007 Jan	17390477
Gateways to clinical trials.	2007 Jan-Feb	17344945
Gateways to clinical trials.	2007 Jul-Aug	17922073
Drug resistant HIV.	2007 Jun 2	17540912
Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis.	2007 Mar 30	17413684
Modelling-based prediction of clinical benefits from etravirine in the TMC125-C223 trial.	2007 Mar-Apr	17507322
Advances in HIV therapeutics: the 14th CROI.	2007 May	17532664
FDA accepts NDA for priority review of TMC125.	2007 Oct	17992720
Antiviral drugs in the treatment of AIDS: what is in the pipeline ?	2007 Oct 15	17933730
NDA submitted for TMC125.	2007 Sep	17939212
Highlights of the 15th Conference on Retroviruses and Opportunistic Infections. Advances in antiretroviral therapy.	2008 Apr-May	18441381
Follow-up of a multi-drug resistant HIV-1 infected patient successfully treated with darunavir and etravirine.	2008 Aug	18551616
FDA approves new HIV drug after priority review.	2008 Feb	18260807
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
3D-QSAR models on clinically relevant K103N mutant HIV-1 reverse transcriptase obtained from two strategic considerations.	2008 Feb 1	18155520
How developing world concerns need to be part of drug development plans: a case study of four emerging antiretrovirals.	2008 Jul	18598916
New treatment options for HIV salvage patients: an overview of second generation PIs, NNRTIs, integrase inhibitors and CCR5 antagonists.	2008 Jul	18556070
Potential for new antiretrovirals to address unmet needs in the management of HIV-1 infection.	2008 Jun	18479200
FDA approval: etravirine.	2008 Mar	18399012
Pharmacokinetic and pharmacodynamic study of the concomitant administration of methadone and TMC125 in HIV-negative volunteers.	2008 Mar	18195053
Successful rescue therapy with Raltegravir (MK-0518) and Etravirine (TMC125) in an hiv-infected patient failing all four classes of antiretroviral drugs.	2008 May	18373415
Is there a role for etravirine in patients with Nonnucleoside reverse transcriptase inhibitor resistance?	2008 May 11	18453859
Shifting paradigms: the resistance profile of etravirine.	2008 Oct	18567574
A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations.	2008 Sep	18571246
Evolution of genetic diversity and drug resistance mutations in HIV-1 among untreated patients from Mali between 2005 and 2006.	2008 Sep	18556706

Patents

Sample Use Guides

In Vivo Use Guide

200 mg (two 100 mg tablets) taken twice daily following a meal

Route of Administration: Oral

In Vitro Use Guide

TMC125, was highly active against wild-type HIV-1 (50% effective concentration [EC50] = 1.4 to 4.8 nM) and showed some activity against HIV-2 (EC50 = 3.5 microM). TMC125 also inhibited a series of HIV-1 group M subtypes and circulating recombinant forms and a group O virus.

Name

Type

Language

ETRAVIRINE

Official Name

English

ETRAVIRINE [JAN]

Common Name

English

ETRAVIRINE [INN]

Common Name

English

TMC 125

Code

English

ETRAVIRINE [MI]

Common Name

English

ETRAVIRINE [MART.]

Common Name

English

INTELENCE

Brand Name

English

ETRAVIRINE [VANDF]

Common Name

English

R165335

Code

English

ETRAVIRINE [WHO-DD]

Common Name

English

BENZONITRILE, 4-((6-AMINO-5-BROMO-2-((4-CYANOPHENYL)AMINO)-4-PYRIMIDINYL)OXY)-3,5-DIMETHYL-

Systematic Name

English

4-((6-AMINO-5-BROMO-2-((4-CYANOPHENYL)AMINO)-4-PYRIMIDINYL)OXY)-3,5-DIMETHYL-BENZONITRILE

Systematic Name

English

TMC125

Code

English

ETRAVIRINE [USAN]

Common Name

English

TMC-125

Code

English

ETRAVIRINE [EMA EPAR]

Common Name

English

ETRAVIRINE [ORANGE BOOK]

Common Name

English

R-165335

Code

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

INTELENCE (AUTHORIZED: HIV INFECTIONS)