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Aplaviroc

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Chemical compound

Pharmaceutical compound

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	461443-59-4^Y HCl: 461023-63-2^Y
PubChemCID	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
(verify)

Aplaviroc (INN, codenamedAK602 andGSK-873140) is aCCR5 entry inhibitor that belongs to a class of2,5-diketopiperazines^[1] developed for the treatment ofHIV infection.^[2]^[3] It was developed byGlaxoSmithKline.

In October 2005, all studies of aplaviroc were discontinued due toliver 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]

References

[edit]

^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.
^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 fromthe original(PDF) on November 3, 2005.
^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.
^"Aplaviroc (GSK-873,140)". AIDSmeds.com. October 25, 2005. Archived fromthe original on January 13, 2007. RetrievedSeptember 5, 2008.
^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.
^Moyle G (December 19, 2006)."The Last Word on Aplaviroc: A CCR5 Antagonist With Poor Efficacy". The Body. Archived fromthe original on 6 October 2008. RetrievedSeptember 5, 2008.
^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.

Uncoating inhibitors	TRIM5alpha (gene)
Transcription inhibitors	Tat antagonists
Translation inhibitors	Trichosanthin
BNAbs	Elipovimab
Other	Abzyme BIT225^† Calanolide A Ceragenin Cyanovirin-N Diarylpyrimidines Epigallocatechin gallate (EGCG) Foscarnet Fosdevirine^† Griffithsin Hydroxycarbamide KP-1461^† Miltefosine North-methanocarbathymidine Portmanteau inhibitors Scytovirin Seliciclib^† Synergistic enhancers Tre recombinase Zinc finger protein transcription factor
Failed agents	Aplaviroc Atevirdine Brecanavir Capravirine Dexelvucitabine Droxinavir Lasinavir Emivirine Lersivirine Lodenosine Loviride Mozenavir Palinavir Telinavir

^#WHO-EM
^‡Withdrawn from market
Clinical trials:
- ^†Phase III
- ^§Never to phase III

°DHHSrecommendedinitial regimen options.^◊Formerly or rarely used agent.

Chemokine receptor modulators

CCR1	Agonists:CCL4 (MIP-1β) CCL5 (RANTES) CCL6 CCL9 (CCL10) CCL14 CCL15 CCL16 CCL23
CCR2	Agonists:CCL2 CCL8 CCL12 CCL16 NAMs:Cenicriviroc (TAK-652, TBR-652)
CCR3	Agonists:CCL5 (RANTES) CCL7 CCL11 CCL13 CCL15 CCL18 CCL24 CCL26 CCL28
CCR4	Agonists:CCL3 (MIP-1α) CCL5 (RANTES) CCL17 CCL22 Antibodies:Mogamulizumab (against CCR4)
CCR5	Agonists:CCL3 (MIP-1α) CCL4 (MIP-1β) CCL5 (RANTES) CCL8 CCL11 CCL13 CCL14 CCL16 NAMs:Aplaviroc Cenicriviroc (TAK-652, TBR-652) INCB009471 Maraviroc Vicriviroc Antibodies:PRO-140
CCR6	Agonists:CCL20
CCR7	Agonists:CCL19 CCL21
CCR8	Agonists:CCL1 CCL16
CCR9	Agonists:CCL25
CCR10	Agonists:CCL27 CCL28
CCR11	Agonists:CCL19 CCL21 CCL25
Ungrouped	Antibodies:Bertilimumab (against CCL11) Carlumab (against CCL2)

CXC

CXCR1 (IL-8Rα)	Agonists:CXCL6 Emoctakin Interleukin-8 (CXCL8, GCP-1) Antagonists:Navarixin NAMs:Ladarixin Reparixin (repertaxin)
CXCR2 (IL-8Rβ)	Agonists:CXCL1 (MGSA) CXCL2 CXCL3 CXCL5 CXCL6 CXCL7 Emoctakin Garnocestim Interleukin-8 (CXCL8, GCP-1) Antagonists:Danirixin Elubrixin Navarixin NAMs:Ladarixin Reparixin (repertaxin)
CXCR3	Agonists:CXCL4 (PF4) CXCL9 (MIG) CXCL10 (IP-10) CXCL11 (I-TAC) Iroplact Antibodies:Eldelumab (against CXCL10)
CXCR4	Agonists:MIF SDF-1 (CXCL12) Ubiquitin Antagonists:Mavorixafor Plerixafor (AMD3100) Antibodies:Ulocuplumab (against CXCR4)
CXCR5	Agonists:CXCL13
CXCR6	Agonists:CXCL16
CXCR7	Agonists:Conolidine CXCL11 (I-TAC) CCX771 LIH383 RTI-5152-12 SDF-1 (CXCL12) VUF15485 PAMs:Plerixafor (AMD3100)