APLAVIROC HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C33H43N3O6.ClH
Molecular Weight	614.172
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.[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=QNNBMSGFNQRUEH-PQQSRXGVSA-N

InChI=1S/C33H43N3O6.ClH/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);1H/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

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

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
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
CCR5 antagonists in the treatment of treatment-naive patients infected with CCR5 tropic HIV-1.	2007 Oct 15	17933724
Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization.	2007 Sep 28	17635930
Functional assays as prismatic views of drug activity: relevance to new drug discovery.	2008	18437634
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
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
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 15:35:19 GMT 2023` Edited by `admin` on `Fri Dec 15 15:35:19 GMT 2023`
Record UNII	04D148Z3VR
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

APLAVIROC HYDROCHLORIDE

Official Name

English

Aplaviroc hydrochloride [WHO-DD]

Common Name

English

4-(4-(((3R)-1-BUTYL-3-((R)-CYCLOHEXYLHYDROXYMETHYL)-2,5-DIOXO-1,4,9- TRIAZASPIRO(5.5)UNDEC-9-YL)METHYL)PHENOXY)BENZOIC ACID HYDROCHLORIDE

Systematic Name

English

APLAVIROC HCL

Common Name

English

APLAVIROC HYDROCHLORIDE [USAN]

Common Name

English

GW873140A

Code

English

APLAVIROC HYDROCHLORIDE [MI]

Common Name

English

BENZOIC ACID, 4-(4-(((3R)-1-BUTYL-3-((R)-CYCLOHEXYLHYDROXYMETHYL)-2,5-DIOXO-1,4,9-TRIAZASPIRO(5.5)UNDEC-9-YL)METHYL)PHENOXY)-, MONOHYDROCHLORIDE

Common Name

English

GW-873140A

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C1660