Aplaviroc

Aplaviroc

Clinical data
Routes of administration	Oral
ATC code	none
Legal status
Legal status	Development terminated
Identifiers
IUPAC name 4-(4-{{#parsoidfragment:1}}{[(3R)-1-butyl-3-[(R)-cyclohexylhydroxymethyl]-2,5-dioxo- 1,4,9-triazaspiro[5.5]undecan-9-yl]methyl}phenoxy)benzoic acid
CAS Number	461443-59-4  Y HCl:  461023-63-2  Y
PubChem CID	3001322
IUPHAR/BPS	805
ChemSpider	2272720  Y
UNII	98B425P30V HCl:  04D148Z3VR  Y
KEGG	D06557  Y
ChEMBL	ChEMBL1255794
CompTox Dashboard (EPA)	DTXSID6047317
Chemical and physical data
Formula	C33H43N3O6
Molar mass	577.722 g·mol−1
3D model (JSmol)	Interactive image
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
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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 (July 2012). "2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products". Chemical Reviews. 112 (7): 3641–3716. Bibcode:2012ChRv..112.3641B. doi:10.1021/cr200398y. PMID   22575049.
2. Maeda K, Ogata H, Harada S, Tojo Y, Miyakawa T, Nakata H, et al. (2004). Determination of binding sites of a unique CCR5 inhibitor AK602 on human CCR5 (PDF). 11th conference on retroviruses and opportunistic infections. San Francisco, CA. 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): 2087–2096. 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): 858–865. doi:10.1128/aac.00821-07. PMC   2258506 . PMID   18070967.
6. Moyle G (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): 110–113. doi:10.1007/s15010-006-6206-1. PMID   16703305. S2CID   38463200.