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

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
The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor.	2005 Apr	15644495
GlaxoSmithKline ends aplaviroc trials.	2006 Mar 21	16514292
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
Antiviral activity and safety of aplaviroc with lamivudine/zidovudine in HIV-infected, therapy-naive patients: the ASCENT (CCR102881) study.	2008	18505181
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
Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists.	2008 Mar	18096812
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

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.

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