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

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	MOL RATIO 1 MOL RATIO (average)

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

Description

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

Show entries

Title	Date	PubMed
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
Potential use of rapamycin in HIV infection.	2010 Dec	21175433
HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry.	2010 Jan	20055594
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

Showing 1 to 5 of 5 entries

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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.