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Review criteria
PubMed was searched in March 2007 for full papers and abstracts published
in English-language journals using the following keywords alone or in
combination: TNF, rheumatoid arthritis, review, meta-analysis in
humans, metalloproteinase, shedding, ADAM, disintegrin, BMS-561392,
TMI, GW3333, and GI5402. For the chemistry section, Chemical Abstracts
STN database, Adis R&D Insight and Pharmaprojects were searched using the
following terms: TACE and TNF-alpha converting enzyme or convertase
inhibitors. No early time limit was placed on any of the search criteria.
INTRODUCTION
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Cell membrane
TNFRI
TNFRII
sTNF
Etanercept
TACE
inhibitor
TACE
sTNF
Infliximab or
adalimumab
proTNF
TACE
ncprheum_2007_145f1.eps
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Function of protein
Reference
TNF
Mediation of inflammation
14, 15
16, 3941,
49, 50
L-selectin
Leukocyte rolling
16, 50
TNF signaling
Hepatotoxicity
16, 50
Cell adhesion
51
LAG-3
T-cell proliferation
Inflammation
52
Heregulin
Cancer
45, 53
IL-1Ra, IL-15Ra
Mediation of inflammation
Rheumatoid arthritis
16, 50
IL-6R
JAKSTAT signaling
Cancer
16
CD40
Immune modulation
Graft rejection
54
NgR, p75NTR
Neurite outgrowth
CNS diseases
50, 55
Neuregulin isoforms
Tumor-cell proliferation
Cancer
53, 56
Ischemia, thrombosis
5759
Semaphorin 4D
Regulation of angiogenesis
Cancer
60
Regulation of neurochemistry
Alzheimers disease
61, 62
Mucus production
Lung diseases
63, 64
APP
Regulation of neurochemistry
Alzheimers disease
65
Nectin-4A
Unknown
66
Unknown
67
CX3CL1
Chemotaxis
Autoimmune diseases
68
Anticoagulation
Thrombosis
69
VCAM, ICAM-1
Cell adhesion
Inflammation
70, 71
Unknown
72
Pref-1
Unknown
73
Abbreviations: APP, amyloid precursor protein; CNS, central nervous system; CX3CL1, CX3C-chemokine ligand 1; EGF, epidermal growth factor; GPCR,
Gprotein-coupled receptor; GPI, glycoprotein I; GPIb-IX-V, glycoprotein Ib-IX-V; (GP)VI, platelet collagen receptor; IBD, inflammatory bowel disease; ICAM1,
intercellular adhesion molecule 1; IL-1Ra, interleukin 1 receptor antagonist; IL-15Ra, interleukin 15 receptor antagonist; IL-6R, interleukin 6 receptor; JAK,
Janus kinase; LAG3, lymphocyte-activated gene 3; NgR, Nogo receptor; p75NTR, p75 neurotrophin receptor; PAR1, proteinase-activated receptor 1; Pref-1,
preadipocyte factor1; SorLA, neuronal sorting protein-related receptor; STAT, signal transducer and activator of transcription; TACE, TNF-converting enzyme;
TGF-, transforming growth factor ; TNF, tumor necrosis factor; TNFR, TNF receptor; VCAM, vascular cell adhesion molecule 1.
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Originator company
(licensee company)
Mechanism of action
Highest
development phase
Reference
1) GW3333
GSK
Preclinical
17
2) TMI-1
Amgen (Wyeth)
Preclinical
18
3) BMS-561392 (DPC-333)
BMS
TACE inhibition
Phase II
19
4) TMI-2
Wyeth
TACE inhibition
Preclinical
20
5) BMS-566394
BMS
TACE inhibition
Preclinical
21
6) TMI-005 (apratastat)
Wyeth
Phase II
26
7) GW4459
GSK
TACE inhibition
Preclinical
30
BMS
TACE inhibition
Preclinical
34
9) W-3646
Wakanuga
Pharmaceutical Co.
TACE inhibition
Preclinical
37
Vertex
TACE inhibition
Preclinical
38
11) IK682
BMS
TACE inhibition
Preclinical
31
GSK
Nonspecific
metalloproteinase
inhibition
Phase I
24
13) DPC-A38088
BMS
TACE inhibition
Preclinical
32
14) DPH-067517
BMS
TACE inhibition
Preclinical
33
15) R-618
Hoffmann-La Roche
TACE inhibition
Phase I
74
16) CH-138
UCB
Preclinical
Unpublished
Abbreviations: BMS, Bristol-Myers Squibb; GSK, GlaxoSmithKline; MMP, matrix metalloproteinase; TACE, TNF-converting enzyme; TNF, tumor necrosis factor.
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1) GW3333
3) BMS-561392 (DPC-333)
2) TMI-1
O
OH
N
H
N
HO
N
H
HO
H
N
O
OH
CF3
N
HO
H
N
N
O
O
N
H
NH
O
NH
HN
N
H
O
N+
O
HN
9) W-3646
O
N
S
O
N
O
HO
N O
S
O
N
H
N
NH
O
11) IK682
O
O S
SH
N
H
OH
O
OO S
N
S
OH
H
6) TMI-005 (apratastat)
7) GW4459
HN
HO
5) BMS-566394
O
H
N
HO
O HN
N
H
O NH2
4) TMI-2
O
N
H
O O S
N
HN
HO
N
O
Figure 2 Structural representation of preclinical and clinical lead compounds for TACE inhibition. The available structures for
compounds detailed in Table 2 are outlined. The structures for compounds 1216 in Table 2 are unavailable. Abbreviation: TACE,
TNFconverting enzyme.
ncprheum_2007_145f3.eps
june 2008 vol 4 no 6 MOSS ET AL.
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Cell membrane
ADAM TNFRII
TNFRI
Endogenous
neutralizing
receptors
TACE
inhibitor
sTNFRII
sTNFRI
sTNF
TACE
proTNF
ncprheum_2007_145f1.eps
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References
1 Feldmann M et al. (1996) Role of cytokines in
rheumatoid arthritis. Annu Rev Immunol 14: 397440
2 Papadakis KA and Targan SR (2000) Role of cytokines
in the pathogenesis of inflammatory bowel disease.
Annu Rev Med 51: 289298
3 Hochberg MC et al. (2001) Stepping-up from
methotrexate: a systematic review of randomised
placebo controlled trials in patients with rheumatoid
arthritis with an incomplete response to methotrexate.
Ann Rheum Dis 60 (Suppl 3): iii51iii54
4 Voulgari PV and Drosos AA (2006) Adalimumab for
rheumatoid arthritis. Expert Opin Biol Ther 6:
13491360
5 Gartlehner G et al. (2006) The comparative efficacy
and safety of biologics for the treatment of rheumatoid
arthritis: a systematic review and metaanalysis.
JRheumatol 33: 23982408
6 Jobanputra P et al. (2002) The effectiveness of
infliximab and etanercept for the treatment of
rheumatoid arthritis: a systematic review and
economic evaluation. Health Technol Assess 6: 1110
7 Blumenauer B et al. Etanercept for the treatment of
rheumatoid arthritis. Cochrane Database of Systematic
Reviews 2003, Issue 4. Art. No.: CD004525.
doi:10.1002/14651858.CD004525
8 Navarro-Sarabia F et al. Adalimumab for treating
rheumatoid arthritis. Cochrane Database of Systematic
Reviews 2005, Issue 3. Art. No.: CD005113.
doi:10.1002/14651858.CD005113.pub2
9 Quinn MA et al. (2005) Very early treatment with
infliximab in addition to methotrexate in early, poorprognosis rheumatoid arthritis reduces magnetic
resonance imaging evidence of synovitis and damage,
with sustained benefit after infliximab withdrawal:
results from a twelve-month randomized, double-blind,
placebo-controlled trial. Arthritis Rheum 52: 2735
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Acknowledgments
We thank R Black for
comments and suggestions
on the manuscript.
Competing interests
The authors declared no
competing interests.