Aplaviroc

Aplaviroc

Systematic (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
Clinical data
Routes of administration	Oral
Legal status	Development terminated
Identifiers
CAS Number	461023-63-2
ATC code	None
PubChem	CID 3001322
IUPHAR/BPS	805
ChemSpider	2272720
UNII	98B425P30V
KEGG	D06557
ChEMBL	CHEMBL1255794
Chemical data
Formula	C33H43N3O6
Molar mass	577.711 g/mol
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 Key:GWNOTCOIYUNTQP-FQLXRVMXSA-N
(verify)

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.

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

• CCR5 receptor antagonist

References

1. Borthwick AD (2012). "2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products". Chemical Reviews 112 (7): 3641–3716. 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, Hirotomo; Maeda, Kenji; Miyakawa, Toshikazu; 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 γ-Chain-Knocked-Out AIDS Mouse Model". Journal of Virology 79 (4): 2087–96. doi:10.1128/jvi.79.4.2087-2096.2005.
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; 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, Judith; Lazzarin, Adriano; Sloan, Louis; et al. (2008). "Antiviral activity and safety of aplaviroc with lamivudine/zidovudine in HIV-infected, therapy-naive patients: the ASCENT (CCR102881) study". Antiviral Therapy (Lond.) 13 (2): 297–306. PMID 18505181.

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): 110–13. doi:10.1007/s15010-006-6206-1. PMID 16703305.