Biology Reference
In-Depth Information
Other potent but nonselective TACE inhibitors include the clinical
candidates Ro 32-7315 (
33
), and TMI-005 (
34
). Another target that has
received less attention is interleukin-1-converting-enzyme (ICE).
Currently, pralnacasan (
35
), an inhibitor of ICE, is in phase II clinical
trials for osteoarthritis (Rudolphi
et al.
, 2003).
Thalidomide (
36
, see Fig. 6.9), a drug originally used for the
treatment of insomnia and morning sickness, was removed from the
market in the 1960s, because it was discovered to be a teratogen.
However, it has recently been resurrected, because it selectively
interferes with TNFα synthesis by enhancing degradation of TNFα
mRNA, while not interfering with other pro-inflammatory cytokines
(Davey and Ashrafian, 2000, Sampaio
et al.
, 1991).
O
OCH
3
O
H
O
O
O
O
OCH
3
NH
OH
N
O
OAc
N
O
H
OH
O
R
forskolin (
39
)
O
NH
2
R = H, thalidomide (
36
)
R = NH
2,
4-amino thalidomide (
38
)
37
O
OCH
3
NH
2
O
N
N
O
N
O
N
O
N
N
rolipram (
41
)
N
N
O
OH
N
O
N
HO
NH
NO
2
nitraquazone (
42
)
O
OH
O
adenosine (
40
)
denbufylline (
43
)
H
3
CO
N
N
H
3
CO
vesnarinone (
44
)
NH
Fig. 6.9 Some natural and synthetic LPS antagonists that degrade TNFα mRNA or
increase cAMP levels.
O
The phenyl substituted thalidomide analogue
37
and the amino
substituted thalidomide
38
are more potent inhibitors of LPS-stimulated
