APLAVIROC

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C33H43N3O6
Molecular Weight	577.711
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCCCN1C(=O)[C@H](NC(=O)C12CCN(CC3=CC=C(OC4=CC=C(C=C4)C(O)=O)C=C3)CC2)[C@H](O)C5CCCCC5

InChI

InChIKey=GWNOTCOIYUNTQP-FQLXRVMXSA-N

InChI=1S/C33H43N3O6/c1-2-3-19-36-30(38)28(29(37)24-7-5-4-6-8-24)34-32(41)33(36)17-20-35(21-18-33)22-23-9-13-26(14-10-23)42-27-15-11-25(12-16-27)31(39)40/h9-16,24,28-29,37H,2-8,17-22H2,1H3,(H,34,41)(H,39,40)/t28-,29-/m1/s1

HIDE SMILES / InChI

Molecular Formula	C33H43N3O6
Molecular Weight	577.711
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/18676693 | https://retrovirology.biomedcentral.com/articles/10.1186/1742-4690-2-S1-S13 | http://www.pharmatimes.com/news/gsk_abandons_trials_of_hiv_drug_aplaviroc_998806

Aplaviroc (GW873140) is a small-molecule noncompetitive allosteric CCR5 antagonist or HIV entry inhibitor (EI) that binds specifically to human CCR5 and exhibits potent anti-HIV activity in vitro in the nanomolar or subnanomolar range. Aplaviroc has exhibited potent in vivo antiviral activity (1.66 log decrease in viral load at nadir) following 10 days of monotherapy. In vitro studies of antiviral activity demonstrate that aplaviroc is active against HIV isolates from a variety of clades as well as those resistant to current HIV therapies targeting RT, PR, and gp41. However, GlaxoSmithKline has decided to terminate Phase III trials of aplaviroc after encountering additional cases of liver damage in patients taking the drug.

Originator

Approval Year

PubMed

Title	Date	PubMed
Antibody conjugation approach enhances breadth and potency of neutralization of anti-HIV-1 antibodies and CD4-IgG.	2013-05	23427154
Identification and characterization of INCB9471, an allosteric noncompetitive small-molecule antagonist of C-C chemokine receptor 5 with potent inhibitory activity against monocyte migration and HIV-1 infection.	2011-07	21459966
Potential use of rapamycin in HIV infection.	2010-12	21175433
A maraviroc-resistant HIV-1 with narrow cross-resistance to other CCR5 antagonists depends on both N-terminal and extracellular loop domains of drug-bound CCR5.	2010-10	20702642
HIV-1 Entry, Inhibitors, and Resistance.	2010-05	21994672
CCR5: From Natural Resistance to a New Anti-HIV Strategy.	2010-02	21994649
HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry.	2010-01	20055594
Two HIV-1 variants resistant to small molecule CCR5 inhibitors differ in how they use CCR5 for entry.	2009-08	19680536
Rapamycin enhances aplaviroc anti-HIV activity: implications for the clinical development of novel CCR5 antagonists.	2009-07	19501260
The relative activity of "function sparing" HIV-1 entry inhibitors on viral entry and CCR5 internalization: is allosteric functional selectivity a valuable therapeutic property?	2009-03	19064629
Antiviral activity and safety of aplaviroc, a CCR5 antagonist, in combination with lopinavir/ritonavir in HIV-infected, therapy-naïve patients: results of the EPIC study (CCR100136).	2009-02	19200175
CCR5 inhibitors: Emerging promising HIV therapeutic strategy.	2009-01	21938106
[Secondary effects of treatment with maraviroc and other CCR5 antagonists. Potential impact of the CCR5 blocker].	2008-10	19133218
In vitro and clinical investigation of the relationship between CCR5 receptor occupancy and anti-HIV activity of Aplaviroc.	2008-10	18676693
Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors.	2008-08-01	18519143
Chemokine (C-C motif) receptor 5-using envelopes predominate in dual/mixed-tropic HIV from the plasma of drug-naive individuals.	2008-07-31	18614865
Potent synergistic anti-human immunodeficiency virus (HIV) effects using combinations of the CCR5 inhibitor aplaviroc with other anti-HIV drugs.	2008-06	18378711
Binding modes of CCR5-targetting HIV entry inhibitors: partial and full antagonists.	2008-06	18249144
New approaches in the treatment of HIV/AIDS - focus on maraviroc and other CCR5 antagonists.	2008-04	18728830
[CCR5 antagonists: a new class of antiretrovirals].	2008-03	18455055
Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists.	2008-03	18096812
Hepatotoxicity observed in clinical trials of aplaviroc (GW873140).	2008-03	18070967
Antiviral activity and safety of aplaviroc with lamivudine/zidovudine in HIV-infected, therapy-naive patients: the ASCENT (CCR102881) study.	2008	18505181
Functional assays as prismatic views of drug activity: relevance to new drug discovery.	2008	18437634
CCR5 antagonists in the treatment of treatment-naive patients infected with CCR5 tropic HIV-1.	2007-10-15	17933724
CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions--review of the literature.	2007-10-15	17933722
Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization.	2007-09-28	17635930
Allosteric theory: taking therapeutic advantage of the malleable nature of GPCRs.	2007-09	19305797
V3 loop truncations in HIV-1 envelope impart resistance to coreceptor inhibitors and enhanced sensitivity to neutralizing antibodies.	2007-08-24	17722977
Host factors influencing susceptibility to HIV infection and AIDS progression.	2007-07-25	17651505
Maraviroc: the evidence for its potential in the management of HIV.	2007-03-31	21221194
Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry.	2007-03	17182681
Recent advances of CCR5 antagonists.	2006-09	19372835
The effects of ritonavir and lopinavir/ritonavir on the pharmacokinetics of a novel CCR5 antagonist, aplaviroc, in healthy subjects.	2006-09	16934050
Structural and molecular interactions of CCR5 inhibitors with CCR5.	2006-05-05	16476734
Evaluation of the drug interaction potential of aplaviroc, a novel human immunodeficiency virus entry inhibitor, using a modified cooperstown 5 + 1 cocktail.	2006-05	16638741
GlaxoSmithKline ends aplaviroc trials.	2006-03-21	16514292
Human immunodeficiency virus (HIV) entry inhibitors (CCR5 specific blockers) in development: are they the next novel therapies?	2005-11-25	16306033
Trials of aplaviroc halted in treatment-naive patients.	2005-11	16323301
The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor.	2005-04	15644495
Potent anti-R5 human immunodeficiency virus type 1 effects of a CCR5 antagonist, AK602/ONO4128/GW873140, in a novel human peripheral blood mononuclear cell nonobese diabetic-SCID, interleukin-2 receptor gamma-chain-knocked-out AIDS mouse model.	2005-02	15681411
CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection.	2005	16329283
Emerging drug targets for antiretroviral therapy.	2005	16114975
Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro.	2004-08	15280474

Patents

Sample Use Guides

In Vivo Use Guide

HIV-infected male and female subjects (age, 22-60 years; weight, 50-97 kg) were randomized to receive placebo or aplaviroc doses of 200 mg once daily, 200 mg twice daily, 400 mg once daily, or 600 mg twice daily for 10 days.

Route of Administration: Oral

In Vitro Use Guide

R5-tropic HIV replication in PBMCs was inhibited by aplaviroc at an IC50 = 0.28 nM; this equates to a CCR5 RO of ~70%. Conversely, 50% CCR5 RO was achieved at 0.152 nM aplaviroc where ~36% inhibition of HIV replication was observed.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 18:32:28 GMT 2025` Edited by `admin` on `Mon Mar 31 18:32:28 GMT 2025`
Record UNII	98B425P30V
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

AK-602

Preferred Name

English

APLAVIROC

Official Name

English

aplaviroc [INN]

Common Name

English

GSK-873140

Code

English

APLAVIROC [MI]

Common Name

English

GW873140

Code

English

Aplaviroc [WHO-DD]

Common Name

English

GW-873140

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C1660