Aplaviroc
4-(4-{[(3R)-1-butyl-3-[(R)-cyclohexylhydroxymethyl]-2,5-dioxo- 1,4,9-triazaspiro[5.5]undecan-9-yl]methyl}phenoxy)benzoic acid
for the treatment of HIV infection
461023-63-2 of hydrochloride
461443-59-4 (free base)
873140
AK-602
GW-873140
ONO-4128
ono…….innovator
Ono Pharmaceutical Co., Ltd. |
Identifiers | |
---|---|
CAS number | 461023-63-2 |
ATC code | None |
PubChem | CID 3001322 |
ChemSpider | 2272720 |
UNII | 98B425P30V |
KEGG | D06557 |
ChEMBL | CHEMBL1255794 |
Chemical data | |
Formula | C33H43N3O6 |
Mol. mass | 577.711 g/mol |
Aplaviroc (INN, codenamed AK602 and GSK-873140) is a CCR5 entry inhibitor developed for the treatment of HIV infection.[1][2] It is developed by GlaxoSmithKline.
In October 2005, all studies of aplaviroc were discontinued due to liver toxicity concerns.[3][4] Some authors have claimed that evidence of poor efficacy may have contributed to termination of the drug’s development;[5] the ASCENT study, one of the discontinued trials, showed aplaviroc to be under-effective in many patients even at high concentrations.[6]
Aplaviroc hydrochloride, an orally-effective, long-acting chemokine CCR5 receptor antagonist, had been under development by Ono and GlaxoSmithKline for the treatment of HIV infection. In early 2006, the companies discontinued development of the antagonist based on reports of elevated liver function test values from clinical studies.
Originally developed at Ono, aplaviroc was licensed to GlaxoSmithKline in 2003 for development, manufacturing and marketing. GlaxoSmithKline also obtained rights to evaluate the agent in non-HIV conditions worldwide with the exception of Japan, South Korea and Taiwan.
A low-molecular-weight compound, aplaviroc prevents HIV viral infection by blocking the binding of the virus to the CCR5 receptor
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WO 2002074770
0r
http://www.google.com/patents/EP1378510A1?cl=en
Reference example 3(3)
- (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexyl)-1,4,9-triazaspiro[5.5]undecane • hydrochloride
-
[0136]
TLC:Rf 0.32 (butanol:acetic acid:water = 4:2:1);
NMR (CD3OD): δ 4.16 (d, J = 2.0 Hz, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 3.52 (m, 1H), 3.37 (m, 1H), 3.28 (m, 1H), 3.22-3.13 (m, 2H), 2.46-1.93 (m, 6H), 1.80-1.64 (m, 5H), 1.48-1.15 (m, 6H), 1.02-0.87 (m, 5H);
Optical rotation:[α]D +1.22 (c 1.04, methanol, 26°C).
Example 9(54)
- (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane • hydrochloride
-
[0359]
TLC:Rf 0.43(chloroform:methanol = 5:1);
NMR (CD3OD):δ 8.05 (d, J = 9.0 Hz, 2H), 7.61 (d, J = 9.0 Hz, 2H), 7.19 (d, J = 9.0 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 4.38 (s, 2H), 4.17 (d, J = 2.1 Hz, 1H), 4.02 (m, 1H), 3.78 (m, 1H), 3.60-3.40 (m, 3H), 3.30-3.10 (m, 2H), 2.56-1.86 (m, 6H), 1.82-1.60 (m, 5H), 1.52-1.16 (m, 6H), 1.06-0.82 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H).
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http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-9-265
Owing to the special properties of piperazines (increased solubility and H-bond acceptor capability etc.) it is often considered to be a privileged structure and therefore occurs widely, for instance in GlaxoSmithKlines investigational anti-HIV drug aplaviroc (4.37) which, despite being a promising CCR5 receptor antagonist, was discontinued due to hepatotoxicity concerns. In this compound the spirodiketopiperazine unit (4.35) was designed to mimic a type-1 β-turn (4.36) as present in G-protein coupled receptors (Figure 14) [117].
The synthesis of aplaviroc and its analogues can be accomplished via the use of an Ugi multicomponent reaction (Ugi-MCR) [118]. The procedure involved the condensation of piperidone 4.38 and butylamine (4.39) followed by reaction of the resulting imine with isocyanide 4.41 and interception of the nitrilium intermediate with the amino acid4.40 (Scheme 47) [119]. This sequence was completed by structural rearrangement and acid-mediated ring closure to produce the spirocyclic diketopiperazine 4.43. Following debenzylation this material was subjected to a reductive amination finally affording aplaviroc analogues (Scheme 47).