227
(d) of 3-O-acetyl-11-keto-beta-boswellic acid showed 16.3% paw oedema inhibition. 1-Indolizine derivatives and 3-indolizine derivatives (e, f) showed IC 50 < 0.3
μMin a human leukocyte assay. Benzothiophene compounds inhibited LTB 4 and
cysteinyl LT production with an IC 50 < 0.3 μM. Hydroxamic acid-derived 5-LOX
inhibitor with sulphonamide linker was also reported to be a better inhibitor (h).
Cimiracemate A and their derivatives are undergoing further in-depth study.
Cimiracemate A inhibited potato 5-LOX with IC 50 ~ 70 μM (i) (Fig. 9.30) (Hofmann
and Steinhilber 2013).
9.2.3.3 Current Status of Lipoxygeanse Drugs
FDA-approved 5-LOX inhibitory drug was Zileuton, but it exhibits liver toxicity
and has a shorter half-life. Most advanced N-hydroxyurea derivative (Atreleuton;
VIA-2291) drugs are under phase II trials for the treatment of cardiovascular diseases and vascular inflammation (Hofmann and Steinhilber 2013). Setileuton
(MK0633) amino oxadiazole substituted coumarin and completed phase II trials for
asthma, atherosclerosis and COPD. Selective non-redox-type inhibitor PF4191834
(Pfizer) completed phase II trial for asthma and terminated for use in knee arthritis
(Steinhilber and Hofmann 2014). FDA-regulated drug flavocoxid rich in baicalin
and catechin inhibiting COX-2/LOX-5 is under trial for the treatment of knee arthritis. Drugs which are under phase II trials are indicated in Fig. 9.31 (Steinhilber and
Hofmann 2014). Drugs which are under phase III clinical trials include Licofelon
and Veliflapon (DG-031) for knee arthritis and myocardial infarction and stroke,
respectively, which inhibit FLAP (Fig. 9.32).
O
H
N
O
O
O
O
N
CH 3
N
O CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
N
N
N
N
H
H
H
N
NH
O
O
O
O
O
N
H
H
NH
Cl
O
O
H
N S CH 3
CH 3
H 3 C
H 3 C
H 3 C
H 3 C
F 3 C
R 2
N
N
N
N
N +
O -
O
O
R 2 =H,
R 1 =p-F-phenyl, H
O
R 1
O O
F 3 C
HO
H 3 C
H 3 C
H 3 C
H 3 C
F 3 C
O
HO
N N
H
S
N
N
X= CH,N
R 1 = OC 5 H 5 ,NH 2
R 2 = F,OCH 3
N
N
N
O
X
R 1
R 2
N
O
S
N
HO
H 3 C
F 3 C
N
N
R 9
R 8
R 7
R 6
R 4
R 5
R 3
R 2
R 1 = CH 3 , R 2-5 , R 7-12 = H, R 6 = O
R 1
R 12
R 11
R 10
O
O
O
O
O
O
N
N
N
N
S
O
CH 3
N
HO
CH 3
N
H 3 C
H 3 C
H 3 C
CH 3
R
R= CH3, CF3
CH 3
O
OH
Cl
O
N
S
H 3 C
H 3 C
H
N
S
a
b
e
f
g
i
h
c
d
Fig. 9.30 Synthetic 5-LOX inhibitors
9 Anti-inflammatory Molecules: Enzyme Inhibitors
(d) of 3-O-acetyl-11-keto-beta-boswellic acid showed 16.3% paw oedema inhibition. 1-Indolizine derivatives and 3-indolizine derivatives (e, f) showed IC 50 < 0.3
μMin a human leukocyte assay. Benzothiophene compounds inhibited LTB 4 and
cysteinyl LT production with an IC 50 < 0.3 μM. Hydroxamic acid-derived 5-LOX
inhibitor with sulphonamide linker was also reported to be a better inhibitor (h).
Cimiracemate A and their derivatives are undergoing further in-depth study.
Cimiracemate A inhibited potato 5-LOX with IC 50 ~ 70 μM (i) (Fig. 9.30) (Hofmann
and Steinhilber 2013).
9.2.3.3 Current Status of Lipoxygeanse Drugs
FDA-approved 5-LOX inhibitory drug was Zileuton, but it exhibits liver toxicity
and has a shorter half-life. Most advanced N-hydroxyurea derivative (Atreleuton;
VIA-2291) drugs are under phase II trials for the treatment of cardiovascular diseases and vascular inflammation (Hofmann and Steinhilber 2013). Setileuton
(MK0633) amino oxadiazole substituted coumarin and completed phase II trials for
asthma, atherosclerosis and COPD. Selective non-redox-type inhibitor PF4191834
(Pfizer) completed phase II trial for asthma and terminated for use in knee arthritis
(Steinhilber and Hofmann 2014). FDA-regulated drug flavocoxid rich in baicalin
and catechin inhibiting COX-2/LOX-5 is under trial for the treatment of knee arthritis. Drugs which are under phase II trials are indicated in Fig. 9.31 (Steinhilber and
Hofmann 2014). Drugs which are under phase III clinical trials include Licofelon
and Veliflapon (DG-031) for knee arthritis and myocardial infarction and stroke,
respectively, which inhibit FLAP (Fig. 9.32).
O
H
N
O
O
O
O
N
CH 3
N
O CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
N
N
N
N
H
H
H
N
NH
O
O
O
O
O
N
H
H
NH
Cl
O
O
H
N S CH 3
CH 3
H 3 C
H 3 C
H 3 C
H 3 C
F 3 C
R 2
N
N
N
N
N +
O -
O
O
R 2 =H,
R 1 =p-F-phenyl, H
O
R 1
O O
F 3 C
HO
H 3 C
H 3 C
H 3 C
H 3 C
F 3 C
O
HO
N N
H
S
N
N
X= CH,N
R 1 = OC 5 H 5 ,NH 2
R 2 = F,OCH 3
N
N
N
O
X
R 1
R 2
N
O
S
N
HO
H 3 C
F 3 C
N
N
R 9
R 8
R 7
R 6
R 4
R 5
R 3
R 2
R 1 = CH 3 , R 2-5 , R 7-12 = H, R 6 = O
R 1
R 12
R 11
R 10
O
O
O
O
O
O
N
N
N
N
S
O
CH 3
N
HO
CH 3
N
H 3 C
H 3 C
H 3 C
CH 3
R
R= CH3, CF3
CH 3
O
OH
Cl
O
N
S
H 3 C
H 3 C
H
N
S
a
b
e
f
g
i
h
c
d
Fig. 9.30 Synthetic 5-LOX inhibitors
9 Anti-inflammatory Molecules: Enzyme Inhibitors