APLAVIROC

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

[H][C@@]1(NC(=O)C2(CCN(CC3=CC=C(OC4=CC=C(C=C4)C(O)=O)C=C3)CC2)N(CCCC)C1=O)[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
Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro.	2004 Aug	15280474
CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection.	2005	16329283
Emerging drug targets for antiretroviral therapy.	2005	16114975
The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor.	2005 Apr	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 Feb	15681411
Trials of aplaviroc halted in treatment-naive patients.	2005 Nov	16323301
Human immunodeficiency virus (HIV) entry inhibitors (CCR5 specific blockers) in development: are they the next novel therapies?	2005 Sep-Oct	16306033
GlaxoSmithKline ends aplaviroc trials.	2006 Mar 21	16514292
Evaluation of the drug interaction potential of aplaviroc, a novel human immunodeficiency virus entry inhibitor, using a modified cooperstown 5 + 1 cocktail.	2006 May	16638741
Structural and molecular interactions of CCR5 inhibitors with CCR5.	2006 May 5	16476734
Recent advances of CCR5 antagonists.	2006 Sep	19372835
The effects of ritonavir and lopinavir/ritonavir on the pharmacokinetics of a novel CCR5 antagonist, aplaviroc, in healthy subjects.	2006 Sep	16934050
V3 loop truncations in HIV-1 envelope impart resistance to coreceptor inhibitors and enhanced sensitivity to neutralizing antibodies.	2007 Aug 24	17722977
Host factors influencing susceptibility to HIV infection and AIDS progression.	2007 Jul 25	17651505
Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry.	2007 Mar	17182681
Maraviroc: the evidence for its potential in the management of HIV.	2007 Mar 31	21221194
CCR5 antagonists in the treatment of treatment-naive patients infected with CCR5 tropic HIV-1.	2007 Oct 15	17933724
CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions--review of the literature.	2007 Oct 15	17933722
Allosteric theory: taking therapeutic advantage of the malleable nature of GPCRs.	2007 Sep	19305797
Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization.	2007 Sep 28	17635930
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
New approaches in the treatment of HIV/AIDS - focus on maraviroc and other CCR5 antagonists.	2008 Apr	18728830
Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors.	2008 Aug 1	18519143
Chemokine (C-C motif) receptor 5-using envelopes predominate in dual/mixed-tropic HIV from the plasma of drug-naive individuals.	2008 Jul 31	18614865
Potent synergistic anti-human immunodeficiency virus (HIV) effects using combinations of the CCR5 inhibitor aplaviroc with other anti-HIV drugs.	2008 Jun	18378711
Binding modes of CCR5-targetting HIV entry inhibitors: partial and full antagonists.	2008 Jun	18249144
[CCR5 antagonists: a new class of antiretrovirals].	2008 Mar	18455055
Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists.	2008 Mar	18096812
Hepatotoxicity observed in clinical trials of aplaviroc (GW873140).	2008 Mar	18070967
[Secondary effects of treatment with maraviroc and other CCR5 antagonists. Potential impact of the CCR5 blocker].	2008 Oct	19133218
In vitro and clinical investigation of the relationship between CCR5 receptor occupancy and anti-HIV activity of Aplaviroc.	2008 Oct	18676693
Two HIV-1 variants resistant to small molecule CCR5 inhibitors differ in how they use CCR5 for entry.	2009 Aug	19680536
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 Feb	19200175
CCR5 inhibitors: Emerging promising HIV therapeutic strategy.	2009 Jan	21938106
Rapamycin enhances aplaviroc anti-HIV activity: implications for the clinical development of novel CCR5 antagonists.	2009 Jul	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 Mar	19064629
Potential use of rapamycin in HIV infection.	2010 Dec	21175433
CCR5: From Natural Resistance to a New Anti-HIV Strategy.	2010 Feb	21994649
HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry.	2010 Jan	20055594
HIV-1 Entry, Inhibitors, and Resistance.	2010 May	21994672
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 Oct	20702642
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 Jul	21459966
Antibody conjugation approach enhances breadth and potency of neutralization of anti-HIV-1 antibodies and CD4-IgG.	2013 May	23427154

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 `Fri Dec 15 16:36:38 GMT 2023` Edited by `admin` on `Fri Dec 15 16:36:38 GMT 2023`
Record UNII	98B425P30V
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

APLAVIROC

Official Name

English

aplaviroc [INN]

Common Name

English

AK-602

Code

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