RILPIVIRINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H18N6
Molecular Weight	366.4185
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=CC(\C=C\C#N)=CC(C)=C1NC2=NC(NC3=CC=C(C=C3)C#N)=NC=C2

InChI

InChIKey=YIBOMRUWOWDFLG-ONEGZZNKSA-N

InChI=1S/C22H18N6/c1-15-12-18(4-3-10-23)13-16(2)21(15)27-20-9-11-25-22(28-20)26-19-7-5-17(14-24)6-8-19/h3-9,11-13H,1-2H3,(H2,25,26,27,28)/b4-3+

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202022s008lbledt.pdf
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/?term=19933797

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) which is used for the treatment of HIV-1 infections in treatment-naive patients. It is active against wild-type and NNRTI-resistant HIV-1. Rilpivirine is a diarylpyrimidinethat inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Reverse transcriptase/RNaseH (UniProtKB: Q72547) 2 Target ID: Reverse transcriptase/RNaseH (UniProtKB: Q72547) Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202022s008lbledt.pdf	Inhibitor 8297		14.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
HIV-1 infection 151 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202022s008lbledt.pdf	Primary		Approved 8429	EDURANT Approved Use In combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve patients with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy. Launch Date 2011

C_max

Value	Dose	Co-administered	Analyte	Population
0.14 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27187753/	25 mg 1 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered:		RILPIVIRINE plasma	Homo sapiens population: UNHEALTHY age: ADOLESCENT sex: FEMALE / MALE food status: FED
121 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29335895/	25 mg 1 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered:		RILPIVIRINE plasma	Homo sapiens population: PREGNANT age: ADULT sex: FEMALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
2.38 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27187753/	25 mg 1 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered:		RILPIVIRINE plasma	Homo sapiens population: UNHEALTHY age: ADOLESCENT sex: FEMALE / MALE food status: FED
1792 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29335895/	25 mg 1 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered:		RILPIVIRINE plasma	Homo sapiens population: PREGNANT age: ADULT sex: FEMALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.3% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29335895/	25 mg 1 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered:		RILPIVIRINE plasma	Homo sapiens population: PREGNANT age: ADULT sex: FEMALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
150 mg 1 times / day multiple, oral Highest studied dose Dose: 150 mg, 1 times / day Route: oral Route: multiple Dose: 150 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19926964 Page: p.62	unhealthy, 21–66 n = 91 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21–66 Sex: M+F Population Size: 91 Sources: https://pubmed.ncbi.nlm.nih.gov/19926964 Page: p.62	Disc. AE: Alanine aminotransferase increase, Aspartate aminotransferase increased... AEs leading to discontinuation/dose reduction: Alanine aminotransferase increase Aspartate aminotransferase increased Sources: https://pubmed.ncbi.nlm.nih.gov/19926964 Page: p.62
25 mg 1 times / day multiple, oral Recommended Dose: 25 mg, 1 times / day Route: oral Route: multiple Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1	unhealthy n = 686 Health Status: unhealthy Condition: HIV-1 infection Population Size: 686 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1	Disc. AE: Depressive disorders, Suicide attempt... AEs leading to discontinuation/dose reduction: Depressive disorders (severe, 1%) Suicide attempt (0.29%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1
25 mg 1 times / day multiple, oral Recommended Dose: 25 mg, 1 times / day Route: oral Route: multiple Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.3	unhealthy n = 686 Health Status: unhealthy Condition: HIV-1 infection Population Size: 686 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.3	Disc. AE: Rash... AEs leading to discontinuation/dose reduction: Rash (0.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.3
25 mg 1 times / day multiple, oral Recommended Dose: 25 mg, 1 times / day Route: oral Route: multiple Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1	Disc. AE: Fat redistribution, Immune reconstitution syndrome... AEs leading to discontinuation/dose reduction: Fat redistribution Immune reconstitution syndrome Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1

AEs

AE	Significance	Dose	Population
Alanine aminotransferase increase	Disc. AE	150 mg 1 times / day multiple, oral Highest studied dose Dose: 150 mg, 1 times / day Route: oral Route: multiple Dose: 150 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19926964 Page: p.62	unhealthy, 21–66 n = 91 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21–66 Sex: M+F Population Size: 91 Sources: https://pubmed.ncbi.nlm.nih.gov/19926964 Page: p.62
Aspartate aminotransferase increased	Disc. AE	150 mg 1 times / day multiple, oral Highest studied dose Dose: 150 mg, 1 times / day Route: oral Route: multiple Dose: 150 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19926964 Page: p.62	unhealthy, 21–66 n = 91 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21–66 Sex: M+F Population Size: 91 Sources: https://pubmed.ncbi.nlm.nih.gov/19926964 Page: p.62
Suicide attempt	0.29% Disc. AE	25 mg 1 times / day multiple, oral Recommended Dose: 25 mg, 1 times / day Route: oral Route: multiple Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1	unhealthy n = 686 Health Status: unhealthy Condition: HIV-1 infection Population Size: 686 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1
Depressive disorders	severe, 1% Disc. AE	25 mg 1 times / day multiple, oral Recommended Dose: 25 mg, 1 times / day Route: oral Route: multiple Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1	unhealthy n = 686 Health Status: unhealthy Condition: HIV-1 infection Population Size: 686 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1
Rash	0.1% Disc. AE	25 mg 1 times / day multiple, oral Recommended Dose: 25 mg, 1 times / day Route: oral Route: multiple Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.3	unhealthy n = 686 Health Status: unhealthy Condition: HIV-1 infection Population Size: 686 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.3
Fat redistribution	Disc. AE	25 mg 1 times / day multiple, oral Recommended Dose: 25 mg, 1 times / day Route: oral Route: multiple Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1
Immune reconstitution syndrome	Disc. AE	25 mg 1 times / day multiple, oral Recommended Dose: 25 mg, 1 times / day Route: oral Route: multiple Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf Page: p.1

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:68606	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:68606
ChemicalBook	CB81454833	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB81454833
MolPort	MolPort-006-170-051	https://www.molport.com/shop/molecule-link/MolPort-006-170-051
ZINC	ZINC000001554274	http://zinc15.docking.org/substances/ZINC000001554274
eMolecules	10663308	https://www.emolecules.com/cgi-bin/more?vid=10663308

PubMed

Title	Date	PubMed
A series of diaryltriazines and diarylpyrimidines are highly potent nonnucleoside reverse transcriptase inhibitors with possible applications as microbicides.	2004 Oct	15388420
Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1.	2005 Mar 24	15771449
In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).	2005 Mar 24	15771434
Next-generation HIV-1 non-nucleoside reverse transcriptase inhibitors.	2006 Feb	16499282
Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains.	2007 May	17223230
Rilpivirine: a novel non-nucleoside reverse transcriptase inhibitor.	2009 Jul	19548857
TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.	2010 Feb	19933797
Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates.	2012 Aug 23	22856541
Rational design of potent non-nucleoside inhibitors of HIV-1 reverse transcriptase.	2012 Dec 13	23137340
Rilpivirine: a next-generation non-nucleoside analogue for the treatment of HIV infection.	2012 May	22519768
Potential of the novel antiretroviral drug rilpivirine to modulate the expression and function of drug transporters and drug-metabolising enzymes in vitro.	2013 May	23428312
Update on rilpivirine: a new potent non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV replication.	2013 May	23157601
In vitro and in vivo activities of AIC292, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor.	2013 Nov	23959304
Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility.	2013 Sep 15	23937980
Competitive fitness assays indicate that the E138A substitution in HIV-1 reverse transcriptase decreases in vitro susceptibility to emtricitabine.	2014	24419343
In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor.	2014	24379202
Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses.	2014 Feb 1	24412110

Patents

Sample Use Guides

In Vivo Use Guide

25 mg (one 25 mg tablet) taken once daily with a meal, is not recommended for patients less than 12 years of age. With rifabutin co-administration, the Edurant dose should be increased to 50 mg (two tablets of 25 mg each) taken once daily with a meal.

Route of Administration: Oral

In Vitro Use Guide

TMC278 (rilpivirine) showed subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM).

Name

Type

Language

RILPIVIRINE

Official Name

English

Rilpivirine [WHO-DD]

Common Name

English

R278474

Code

English

RILPIVIRINE COMPONENT OF CABENUVA

Brand Name

English

rilpivirine [INN]

Common Name

English

R-278474

Code

English

TMC-278

Code

English

4-{[4-({4-[(1E)-2-Cyanoethenyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile

Systematic Name

English

RILPIVIRINE [USAN]

Common Name

English

RILPIVIRINE [MI]

Common Name

English

EDURANT

Brand Name

English

BENZONITRILE, 4-((4-((4-((1E)-2-CYANOETHENYL)-2,6-DIMETHYLPHENYL)AMINO)-2- PYRIMIDINYL)AMINO)-

Systematic Name

English

CABENUVA COMPONENT RILPIVIRINE

Brand Name

English

RILPIVIRINE [VANDF]

Common Name

English

RILPIVIRINE [MART.]

Common Name

English

RILPIVIRINE [JAN]

Common Name

English

TMC278

Code

English

RILPIVIRINE [ORANGE BOOK]

Common Name

English

Classification Tree Code System Code

WHO-ATC

J05AG05