Aplaviroc

Aplaviroc (INN, codenamed AK602 and GSK-873140) is a CCR5 entry inhibitor that belongs to a class of 2,5-diketopiperazines[1] developed for the treatment of HIV infection.[2][3] It was developed by GlaxoSmithKline.

Aplaviroc
Clinical data
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • Development terminated
Identifiers
IUPAC name
  • 4-(4-{[(3R)-1-butyl-3-[(R)-cyclohexylhydroxymethyl]-2,5-dioxo- 1,4,9-triazaspiro[5.5]undecan-9-yl]methyl}phenoxy)benzoic acid
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC33H43N3O6
Molar mass577.722 g·mol−1
3D model (JSmol)
SMILES
  • CCCCN1C(=O)[C@H](NC(=O)C12CCN(CC2)CC3=CC=C(C=C3)OC4=CC=C(C=C4)C(=O)O)[C@@H](C5CCCCC5)O
InChI
  • 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 Y
  • Key:GWNOTCOIYUNTQP-FQLXRVMXSA-N Y
  (verify)

In October 2005, all studies of aplaviroc were discontinued due to liver toxicity concerns.[4][5] Some authors have claimed that evidence of poor efficacy may have contributed to termination of the drug's development;[6] the ASCENT study, one of the discontinued trials, showed aplaviroc to be under-effective in many patients even at high concentrations.[7]

See also

References
  1. Borthwick AD (July 2012). "2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products". Chemical Reviews. 112 (7): 3641–716. doi:10.1021/cr200398y. PMID 22575049.
  2. Maeda, Kenji; Ogata, Hiromi; Harada, Shigeyoshi; et al. (2004). "Determination of binding sites of a unique CCR5 inhibitor AK602 / ONO-4128/ GW873140 on human CCR5" (PDF). Conference on Retroviruses and Opportunistic Infections. Archived from the original (PDF) on November 3, 2005.
  3. Nakata H, Maeda K, Miyakawa T, Shibayama S, Matsuo M, Takaoka Y, et al. (February 2005). "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". Journal of Virology. 79 (4): 2087–96. doi:10.1128/jvi.79.4.2087-2096.2005. PMC 546550. PMID 15681411.
  4. "Aplaviroc (GSK-873,140)". AIDSmeds.com. October 25, 2005. Archived from the original on January 13, 2007. Retrieved September 5, 2008.
  5. Nichols WG, Steel HM, Bonny T, Adkison K, Curtis L, Millard J, et al. (March 2008). "Hepatotoxicity observed in clinical trials of aplaviroc (GW873140)". Antimicrobial Agents and Chemotherapy. 52 (3): 858–65. doi:10.1128/aac.00821-07. PMC 2258506. PMID 18070967.
  6. Moyle, Graeme (December 19, 2006). "The Last Word on Aplaviroc: A CCR5 Antagonist With Poor Efficacy". The Body. Archived from the original on 6 October 2008. Retrieved September 5, 2008.
  7. Currier J, Lazzarin A, Sloan L, Clumeck N, Slims J, McCarty D, et al. (2008). "Antiviral activity and safety of aplaviroc with lamivudine/zidovudine in HIV-infected, therapy-naive patients: the ASCENT (CCR102881) study". Antiviral Therapy. 13 (2): 297–306. doi:10.1177/135965350801300204. PMID 18505181. S2CID 21839689.

Further reading
  • Horster S, Goebel FD (April 2006). "Serious doubts on safety and efficacy of CCR5 antagonists : CCR5 antagonists teeter on a knife-edge". Infection. 34 (2): 110–3. doi:10.1007/s15010-006-6206-1. PMID 16703305. S2CID 38463200.
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