Indole derivatives as potent inhibitors of 5-lipoxygenase: Design, synthesis, biological evaluation, and molecular modeling

Article abstract of DOI:10.1016/j.bmcl.2007.02.038

A series of novel indole derivatives was designed, synthesized and evaluated by cell-based assays for their inhibitory activities against 5-LOX in rat peritoneal leukocytes. Most of them (30 out of 35) showed an inhibitory potency higher than the initial screening hit 1a (IC₅₀ = 74 μM). Selected compounds for concentration-response studies showed prominent inhibitory activities with IC₅₀ values ranging from 0.74 μM to 3.17 μM. Four compounds (1m, 1s, 4a, and 6a) exhibited the most potent inhibitory activity compared to that of the reference drug (Zileuton), with IC₅₀ values less than 1 μM. Molecular modeling studies for compounds 1a, 3a, 4a, and 6a were also presented. The excellent in vitro activities of this class of compounds may possess potential for the treatment of LT-related diseases.

Full text of DOI:10.1016/j.bmcl.2007.02.038

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2414–2420
Indole derivatives as potent inhibitors of 5-lipoxygenase:
Design, synthesis, biological evaluation, and molecular modeling
Mingfang Zheng,a Mingyue Zheng,a Deju Ye,a Yangmei Deng,b Shuifeng Qiu,b
Xiaomin Luo,a Kaixian Chen,a Hong Liua,* and Hualiang Jianga,c,
*
aDrug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Zhangjiang Hi-Tech Park, Shanghai 201203, China
bZhejiang Respiratory Drugs Research Laboratory of State Drugs Administration of China,
Medical School of Zhejiang University, Hangzhou 310031, China
cSchool of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
Received 5 December 2006; revised 16 January 2007; accepted 15 February 2007
Available online 17 February 2007
Abstract—A series of novel indole derivatives was designed, synthesized and evaluated by cell-based assays for their inhibitory activ-
ities against 5-LOX in rat peritoneal leukocytes. Most of them (30 out of 35) showed an inhibitory potency higher than the initial
screening hit 1a (IC50 = 74 lM). Selected compounds for concentration–response studies showed prominent inhibitory activities
with IC50 values ranging from 0.74 lM to 3.17 lM. Four compounds (1m, 1s, 4a, and 6a) exhibited the most potent inhibitory activ-
ity compared to that of the reference drug (Zileuton), with IC50 values less than 1 lM. Molecular modeling studies for compounds
1a, 3a, 4a, and 6a were also presented. The excellent in vitro activities of this class of compounds may possess potential for the treat-
ment of LT-related diseases.
Ó 2007 Published by Elsevier Ltd.
5-Lipoxygenase (5-LOX) is the key enzyme in the bio-
synthesis of leukotrienes (LTs) through catalyzing the
initial two steps in conversion of arachidonic acid to
LTs.1 LTB4 and the cysteinyl-leukotrienes are potent
constrictors of human airways, and have powerful pro-
inflammatory properties.2 Inhibition of 5-LOX may lead
to the development of new therapeutic treatments for
pathologies such as asthma, allergies, and other inflam-
matory disorders.1,3,4 Recent studies have implicated a
role of 5-LOX products involved in a number of other
diseases, including cancer,5 atherosclerosis,6 stroke,7
and osteoporosis.8 Therapeutic potential of 5-LOX inhi-
bition has been widely highlighted in recent years.9–13
of action. Three different types of inhibitors have been
considered: redox inhibitors, iron chelators, and non-re-
dox inhibitors of 5-LOX.3 Zileuton (Fig. 1) was the first
marketed 5-LOX inhibitor, with an iron chelating mech-
anism, used in the chronic treatment of asthma.14
Although numerous efforts have been done toward
5-LOX in the past two decades, and there is a strong
need for efficient drugs targeting 5-LOX pathway, no
other 5-LOX inhibitor is available on the market cur-
rently.8 Therefore, it is a great challenge to discover
and develop novel efficient compounds as 5-LOX inhib-
itors, without disadvantages of former inhibitors.
Compounds with the indole core have been widely stud-
ied due to their capability of binding to many receptors
with high affinity,15 and a few indole derivatives have
been reported for their inhibitory activities against
5-LOX.3 Recently, Landwehr et al. reported a series of
2-amino-5-hydroxyindole derivatives as inhibitors of hu-
man 5-LOX.16 By screening abundant substituted indole
compounds of our in-house collection, 4-(1-benzyl-1H-
indol-3-yl)-1-morpholinobutan-1-one (1a, Fig. 1) was
identified, with an IC50 value of 74 lM, for inhibiting
5-LOX in the cell-based assay. Using the screening hit
Currently, a huge number of different types of small
molecular inhibitors of 5-LOX have been described in
the literature, classified depending on their mechanism
Keywords: Indole derivatives; 5-Lipoxygenase; Inhibitor; Molecular
modeling.
*
Corresponding authors. Tel.: +86 21 50807042; fax: +86 21 50807088
(H.L.); e-mail addresses: hliu@mail.shcnc.ac.cn; hljiang@mail.shcnc.
ac.cn
0960-894X/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2007.02.038

M. Zheng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2414–2420
2415
Treatment of the commercially available tryptophol with
mesyl chloride (MsCl) in CH2Cl2 formed 2-(1H-indol-3-
yl)ethyl methanesulfonate, which was subsequently
reacted with 3-fluoro-5-(4-methoxytetrahydro-2H-pyr-
O
4
5
N
CH3
N
3
O
6
2
19
S
O
an-4-yl)phenol in the presence of Cs2CO3 in DMF to
N
7
1
HO
NH2
produce the methoxytetrahydropyran derivative 9.
Compound 9 was converted to the N-benzyl product
10 by reacting with BnBr in the presence of NaH in
DMF. Compound 11 was synthesized using indole-3-
propyl carboxyl acid (2d) as the starting material. Acid
2d was esterified in methanol in the presence of H2SO4
to afford the methyl ester 12. N-benzylation of the free in-
dole nitrogen of 12 with BnBr in the presence of NaH in
DMF produced compound 13, which was then reduced
by LiAlH4 in THF to give the indole-3-propyl alcohol
intermediate 14. The hydroxyl of 14 was then activated
by MsCl and reacted with 3-fluoro-5-(4-methoxytetrahy-
dro-2H-pyran-4-yl)phenol in the presence of Cs2CO3 in
DMF to form the target product 11.
Zileuton
1a
F
OMe
O
O
O
N
CH3
ZD-2138
Figure 1. Representative structures of 5-LOX inhibitors and the
screening hit 1a.
All derivatives (1b–t, 3a–e, and 4–11, Table 1) were eval-
uated by the cell-based assay for their inhibitory activi-
ties against 5-LOX in rat peritoneal leukocytes,20 using
Zileuton as the reference drug. As shown in Table 1,
all the compounds showed modest to potent inhibitory
activities against 5-LOX at 5 lM, with the inhibition
range from 15.9% (3c) to 95.4% (6a). Most of them
(30 out of 35) had inhibitory activities higher than that
of the initial lead 1a (25.8% inhibition at 5 lM;
IC50 = 74 lM). Little change in activity was observed
by introducing methyl (1b) or chloro (1c) to the benzyl
of 1a. While, replacing the benzyl substituent with ben-
zoyl (1d), the activity was improved to 58.2% at 5 lM.
When the alkyl linker between the indole core and the
carbonyl moiety was changed from propylene to ethyl-
ene or methylene, the substituents’ effects at the N1 po-
sition of 1a were not in accordance with the derivatives
with propylene linker derivatives (1a–e). The N1-benzyl
derivative (1f) showed the most potent inhibitory activ-
ity among the compounds with ethylene linker (1f–j),
with 63.8% inhibition at 5 lM. However, the N1-3,4-
dichlorobenzyl derivative (1m) exhibited the most potent
activity (81.9% inhibition at 5 lM) among the com-
pounds with a methylene linker (1k–o) in the cell-based
assay. Introducing methoxy or chloro substituents to the
C5 position of the indole core (1p–t) also showed posi-
tive results. p-Chloro benzoyl substituent at the N1 po-
sition (1r) was more preferred than the corresponding
benzyl substituted ones (1p–q) by the 5-methoxy indole
core, with 1r exhibiting 70.2% inhibition at 5 lM. On
the contrary, when the 5-methoxy indole core was chan-
ged to the 5-chloro indole core, the N1-benzyl substi-
tuted derivative (1s, 80.2% inhibition at 5 lM) was
more potent than the p-chloro benzoyl substituted one
(1t, 37.9% inhibition at 5 lM). Results of N1 unsubsti-
tuted derivatives 3a–e suggested that the inhibitory
activity was affected greatly by the length of the alkyl
linker between the indole core and the carbonyl moiety,
and the propylene linker was preferred, regardless of the
substituents in C5 position (CH3O, Cl) of the indole.
1a as the benchmark compound, a series of novel indole
derivatives (1b–t, 3a–e, and 4–11, Table 1) was designed,
synthesized, and evaluated by the cell-based assay for
their inhibitory activities against 5-LOX in rat perito-
neal leukocytes. Molecular modeling studies were also
carried out to investigate their binding interactions with
5-LOX.
Using different aryl groups substituted at the N1 posi-
tion of 1a, we synthesized compounds 1b–e. Derivatives
1f–o were designed by changing the length of the alkyl
linkers between the indole core and the carbonyl moiety,
using methylene or ethylene displacing the propylene
linker of 1a–e. Substituting the 2,5-positions of the in-
dole core of 1a–e with methyl, methoxy or chloro sub-
stituents, respectively, analogues 1p–t were obtained.
Compounds 3a–e are the precursors of compounds 1
with no substitution at the N1 position. Using the
Boc-piperazine, piperazine or 1-methanesulfonylpiper-
azine instead of the morpholino units of 1a, 1p, 3a,
and 3d, we prepared analogues 4–7 (Table 1). Com-
pound 8 is the reduction product of 1a. The methoxy-
tetrahydropyran moiety of ZD-2138 (Fig. 1) was a
frequently reported pharmacophore of 5-LOX devoid
of redox and iron-chelating properties.17 Compounds
9–11 (Scheme 2) were designed and synthesized by intro-
ducing the non-redox 5-LOX pharmacophore to the
3-position of the indole core.
The synthesis of this class of indole derivatives is out-
lined in Schemes 1 and 2. Condensation of the appropri-
18
ately substituted indole-3-carboxyl acid 2a–e
with
morpholine or Boc-piperazine afforded derivatives 3a–
e, and 4a–b, which were subsequently reacted with var-
ious benzyl or benzoyl chlorides, respectively, in the
presence of NaH in DMF, to produce derivatives 1b–t
and 5a–b. Deprotection of 5a–b using 50% TFA in
dichloromethane afforded 6a–b. Treatment of 6a with
mesyl chloride in pyridine gave the derivative 7. Reduc-
tion the carbonyl of 1a to a methylene by LiAlH4 in
THF afforded the derivative 8.
An important advance in activity was achieved (95%
inhibition at 5 lM) when the morpholino unit at the

2416
M. Zheng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2414–2420
Table 1. Structures and inhibitory activities against 5-LOX in rat peritoneal leukocytes of indole derivatives
O
(CH2)n
R1
N
R2
N
X
R3
1a–t, 3–7
Compound
R1
R2
R3
X
n
%Inhibition at 5 lMa
1a
1b
1c
1d
1e
1f
H
H
Benzyl
O
2
2
2
2
2
1
1
1
1
1
0
0
0
0
0
2
2
2
2
2
2
1
0
2
2
2
2
2
2
2
2
2
25.8
33.9
26.7
58.2
32.4
63.8
23.4
55.2
38.5
26.0
41.4
21.0
81.9
34.6
22.4
54.2
26.4
70.2
80.2
37.9
62.3
33.0
15.9
72.9
71.3
84.1
71.2
38.2
51.5
95.4
64.6
23.9
H
H
p-Methylbenzyl
3,4-Dichlorobenzyl
Benzoyl
O
H
H
O
H
H
O
H
H
p-Chlorobenzoyl
Benzyl
Benzoyl
O
H
H
O
1g
1h
1i
H
H
O
H
H
p-Methylbenzyl
3,4-Dichlorobenzyl
p-Chlorobenzoyl
Benzyl
O
H
H
O
1j
H
H
O
1k
1l
H
H
O
H
H
Benzoyl
O
1m
1n
1o
1p
1q
1r
1s
1t
H
H
3,4-Dichlorobenzyl
p-Methylbenzyl
p-Chlorobenzoyl
Benzyl
O
H
H
O
H
H
O
OCH3
OCH3
OCH3
Cl
CH3
CH3
CH3
CH3
CH3
H
O
p-Methylbenzyl
p-Chlorobenzoyl
Benzyl
O
O
O
Cl
H
p-Chlorobenzoyl
H
O
3a
3b
3c
3d
3e
4a
4b
5a
5b
6a
6b
7
O
H
H
H
O
H
H
H
O
OCH3
Cl
CH3
CH3
H
H
O
H
O
H
H
BocN
BocN
BocN
BocN
NH
NH
MsN
OCH3
H
CH3
H
H
Benzyl
OCH3
H
CH3
H
Benzyl
Benzyl
OCH3
H
CH3
H
Benzyl
Benzyl
(CH2)n
R1
N
R2
N
R3
X
8
H
H
Benzyl
O
2
41.6
(CH2)n
R2
O
F
R1
OMe
N
R3
O
9
10
H
H
H
1
1
2
64.2
31.8
46.5
86.9
H
OCH3
H
CH3
Benzyl
Benzyl
11
Zileuton
a Values are means of three determinations and deviation from the mean is <10% of the mean value (Catalog No. 520111, Cayman Chemicals Inc.).
C3 position of 1a was replaced by a piperazine (6a). Its
N1 unsubstituted precursor 4a also exhibited outstand-
ing activity, with 84.1% inhibition at 5 lM. Mesylation
of 6a led to a tremendous decrease in ability against 5-
LOX product synthesis, as shown by 7 (23.9% inhibi-
tion at 5 lM). Little improvement in activity was ob-
served with the reduction of carbonyl in 1a to a
methylene (8). When the methoxytetrahydropyran

M. Zheng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2414–2420
2417
O
N
O
(CH2)n
R2
(CH2)n
(CH2)n COOH
R2
R1
R1
R1
N
R2
c
a
N
R3
O
N
H
O
N
H
3a-e
1b-t
2a-e
n = 0, 1, 2
n = 0, 1, 2
R
R
n = 0, 1, 2
1 = H, OCH3 or Cl
1 = H, OCH3 or Cl
2 = H or CH3
R
R
R
1 = H, OCH3 or Cl
R2 = H or CH3
2 = H or CH3
R3 = various benzyl of benzoyl
b
f
O
O
N
(CH2)2
R2
(CH2)2
N
(CH2)2
R2
R1
R1
N
c
N
NBoc
N
N
H
O
NBoc
4a: R1 = H, R2 = H
4b: R1 = OCH3, R2 = CH3
5a: R1 = H, R2 = H
5b: R1 = OCH3, R2 = CH3
8
d
O
N
O
(CH2)2
(CH2)2
R1
N
R2
e
N
NSO2CH3
N
NH
6a: R1 = H, R2 = H
7
6b: R1 = OCH3, R2 = CH3
Scheme 1. Synthetic routes of indole derivatives 1b–t and 3–8. Reagents and conditions: (a) EDCI, DMAP, morpholine, DMF; (b) Boc-piperazine,
EDCI, DMAP, DMF; (c) NaH, R3Cl, DMF; (d) TFA, CH2Cl2; (e) MsCl, Py; (f) LiAlH4, THF.
pharmacophore of 5-LOX was introduced to the C3
position (9-11), their activities were improved in com-
parison with 1a. Among them, compound 9, which
had no substitution at the N1 position, was the most
potent one, with 64.2% inhibition at 5 lM. So far, it
seems that the N1 unsubstituted case was presumed
to exhibit good inhibitory activities.
ties (IC50s less than 1 lM) comparable to that of
Zileuton (0.83 lM), which was in accordance with
the previous report.21
Molecular modeling experiments were carried out to
investigate the binding interactions between this series
of compounds and the active site of 5-LOX. As de-
scribed in our previous report,22 3D-model of 5-LOX
was generated by homology modeling, based on rabit
To determine the exact potency of the compounds
that demonstrated significant inhibitory activities
against 5-LOX at 5 lM, 10 compounds were selected
(1f, 1m, 1r–s, 3a, 3d–e, 4a, 6a, and 9) for further
investigation in concentration–response studies, and
the results are summarized in Table 2. All these com-
pounds concentration-dependently inhibited 5-LOX
product synthesis and showed prominent inhibitory
activities with IC50 values ranging from 0.74 lM to
3.17 lM, which were 20 to 100 times more active than
the initial screening hit 1a (IC50 = 74 lM). Derivatives
1m, 1s, 4a, and 6a showed excellent inhibitory activi-
˚
reticulocyte 15-LOX (PDB entry 1LOX at 2.40 A reso-
lution), which were found with sequence similarities of
40.68% to the target protein 5-LOX by using the
BLAST software.23 The missing atoms of residues 210,
211, 601, 602, and 177–187 of 15-LOX in its crystal
structure were added with the Loop/Search module of
InsightII,24 followed by a loop relaxing. Then 10 of
3D models of 5-LOX were generated based on the coor-
dinates of 15-LOX using MODELLER,25 and all these
3D structures were optimized with conjugate gradient
minimization scheme followed by a restrained simulated

2418
M. Zheng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2414–2420
F
F
O
O
OH
O
b
a
1)
N
MeO
N
H
O
MeO
N
H
9
10
O
O
O
C2H4COOCH3
CH3
C2H4COOCH3
CH3
C2H4COOH
CH3
c
b
2)
N
N
H
N
H
2d
12
13
O
O
O
C2H4CH2OH
CH3
OMe
O
d
a
CH3
N
N
F
14
11
Scheme 2. Synthetic routes of methoxytetrahydropyran attached indole derivatives 9–11. Reagents and conditions: (a) (1) MsCl, CH2Cl2; (2) 3-
fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenol, Cs2CO3, DMF; (b) NaH, BnBr, DMF; (c) MeOH, H2SO4, reflux; (d) LiAlH4, THF.
Table 2. Determination of IC50 values of selected compoundsa
phobic residues, except for Asn554 and four iron ligand
residues around the iron center. Molecular modeling
studies between the 5-LOX and compounds 1a, 3a, 4a,
and 6a were carried out by using AutoDock 3.0.3 pro-
Compound
IC50 (lM)
1a
74.0
3.17
0.87
2.25
0.95
2.06
3.16
1.33
0.74
0.85
2.38
0.83
1f
1m
gram,27,28 and the docking parameters in our previous
29
study
were adopted. For each compound, twenty
1r
1s
3a
possible binding conformations were generated, and
the conformation with the lowest predicted binding free
energy of the most occurring binding modes in 5-LOX
active pocket was selected for further analysis. Figure
2 demonstrates the results of their binding modes.
3d
3e
4a
6a
9
Zileuton
Two different conformations have been found for the
four compounds in the 5-LOX active pocket. As shown
in Figure 2(A), compounds 1a and 6a, which have benzyl
substitution at the N1 position, adopt an extended con-
formation, with the long subunit at C3 position extend-
ing deep into the cleft, in close proximity to Asn425.
Whereas, a folded conformation shown in Figure 2(B)
is taken by the N1-unsubstituted derivatives 3a and 4a,
which fit well in the central hydrophobic part of the
5-LOX active site with their long subunits at C3 position
bend back to the indole rings. The indole ring of com-
pounds 1a and 6a is positioned in the middle of the cav-
ity, interacting strongly with Leu368 and Leu607, and
the phenyl group points to the entrance of the active
pocket, having strong interactions with Ala410. The
protonized NH of 6a undergoes a strong hydrogen bond
a Values are means of three determinations and deviation from the
mean is <10% of the mean value (Catalog No. 520111, Cayman
Chemicals Inc.).
annealing molecular dynamics simulation. The model
with the lowest value of the objective function was se-
lected as a representative model for further study. More
details of model equilibration by molecular dynamics
have been described in our previous report.22
In accordance with a recent report,26 the 5-LOX active
site of our 3D-model consists of a deep bent-shaped cleft
containing the non-heme iron cofactor. The bottom of
the substrate binding pocket is defined by the side chains
of Phe359, L420, Ala424, Asn425, and Ala603, and the
wall of the binding channel is mainly lined with hydro-
with Od1 of Asn425 (distance = 2.14 A). This may
˚
contribute to the better IC50 value of 6a (0.85 lM)
than the corresponding morpholino derivative 1a

M. Zheng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2414–2420
2419
Figure 2. Binding models of compounds 1a, 3a, 4a and 6a in the binding cleft of 5-lipoxygenase via homology modeling. The left part (A) describes
the binding models of compounds 1a (green) and 6a (yellow). The right part (B) shows the binding models of compounds 3a (pink) and 4a (blue).
(IC50 = 74 lM). However, in the folded conformation of
compounds 3a and 4a, the indole rings are closely adja-
cent to Leu414, forming strong hydrophobic interactions
with the isobutyl side chain of Leu414, and the alkyl
linkers interact with the Ala410. The better inhibitory
activity of 4a (IC50 = 0.74 lM), in comparison with 3a
(IC50 = 2.06 lM), might be ascribed to the favorable
hydrogen bond formed between the oxygen atom of
the carbonyl of 4a with the hydroxyl of the carboxyl of
Science and Technology Commission, the Key Project
from the Shanghai Science and Technology Commission
(Grant 02DJ14006), the Key Project for New Drug Re-
search from CAS, and the 863 Hi-Tech Programm
(Grants 2006AA020602, 2006AA02Z336).
References and notes
˚
1. Samuelson, B. Science 1983, 220, 568.
2. Funk, C. D. Science 2001, 294, 1871.
Ile 673 (distance = 2.61 A). Additionally, the Boc part
of 4a also increases hydrophobic interactions between
4a and the binding site of 5-LOX. It was noteworthy that
the results of our docking studies were in agreement with
the experimental data quite well, which validated the effi-
ciency of our homology model of human 5-LOX.
3. Young, R. N. Eur. J. Med. Chem. 1999, 34, 671.
4. Drazen, J. Am. J. Respir. Crit. Care Med. 1998, 157, S233.
5. Romano, M.; Claria, J. FASEB J. 2003, 17, 1986.
6. Spanbroek, R.; Habenicht, A. J. Drug News Perspect.
2003, 16, 485.
7. Helgadottir, A.; Manolescu, A.; Thorleifsson, G.; Gre-
tarsdottir, S.; Jonsdottir, H.; Thorsteinsdottir, U.; Samani,
N. J.; Gudmundsson, G.; Grant, S. F.; Thorgeirsson, G.;
Sveinbjornsdottir, S.; Valdimarsson, E. M.; Matthiasson,
S. E.; Johannsson, H.; Gudmundsdottir, O.; Gurney, M.
E.; Sainz, J.; Thorhallsdottir, M.; Andresdottir, M.;
Frigge, M. L.; Topol, E. J.; Kong, A.; Gudnason, V.;
Hakonarson, H.; Gulcher, J. R.; Stefansson, K. Nat.
Genet. 2004, 36, 233.
8. Werz, O.; Steinhilber, D. Biochem. Pharmacol. 2005, 70,
327.
9. Balkan, A.; Berk, B. Curr. Med. Chem. Anti-Inflamm.
Anti-Allergy Agents 2003, 2, 9.
In summary, a series of novel indole derivatives was de-
signed and synthesized based on the initial hit 1a. All
the compounds were evaluated by the cell-based assay
for their inhibitory ability against 5-LOX in rat peritoneal
leukocytes. Most of the compounds (30 out of 35) exhib-
ited inhibitory potency higher than that of compound 1a.
Selected compounds for concentration–response studies
showed prominent inhibitory activities with IC50 values
ranging from 0.74 lM to 3.17 lM, which were 20 to 100
times more active than 1a (IC50 = 74 lM). Compounds
1m, 1s, 4a, and 6a showed potency comparable to that
of Zileuton, with IC50 values less than 1 lM. Molecular
modeling studies for compounds 1a, 3a, 4a, and 6a were
in agreement with the experimental data quite well. The
excellent in vitro activities of this class of compounds
may possess potential for the treatment of LT-related dis-
eases. Further studies are in progress.
´
´
10. Julemont, F.; Dogne, J.-M.; Laeckmann, D.; Pirotte, B.;
de Laval, X. Expert Opin. Ther. Patents 2003, 13, 1.
11. Werz, O.; Steinhilber, D. Expert Opin. Ther. Patents 2005,
15, 505.
12. Funk, C. D. Nat. Rev. 2005, 4, 664.
13. Yoshimura, R.; Matsuyama, M.; Kuratsukuri, K.; Tsuch-
ida, K.; Takemoto, Y.; Nakatani, T. Drugs Future 2005,
30, 351.
14. Drazen, J. M.; Israel, E.; O’Byrne, P. M. N. Engl. J. Med.
1999, 340, 197.
15. Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106,
2875.
Acknowledgments
We gratefully acknowledge financial support from the
National Natural Science Foundation of China (Grants
30672539, 20572117, and 20472094), the Basic Research
Project for Talent Research Group from the Shanghai
16. Landwehr, J.; George, S.; Karg, E.-M.; Poeckel, D.;
Steinhilber, D.; Troschuetz, R.; Werz, O. J. Med. Chem.
2006, 49, 4327.
17. Charlier, C.; Michaux, C. Eur. J. Med. Chem. 2003, 38, 645.

2420
M. Zheng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2414–2420
18. Menciu, C.; Duflos, M.; Fouchard, F.; Le Baut, G.; Emig,
P.; Achterrath, U.; Szelenyi, B.; Nickel, B.; Schmidt, J.;
24. Insight II. UserGuide, MSI Inc., San Diego, USA,
2000.
ˇ
25. Sali, A. Mol. Med. Today 1995, 1, 270.
Kutscher, B.; Gunther, E. J. Med. Chem. 1999, 42, 638.
¨
´
19. Crawley, G. C.; Dowell, R. I.; Edwards, P. N.; Foster, S.
J.; McMillan, R. M.; Walker, E. R. H.; Waterson, D.
J. Med. Chem. 1992, 35, 2600.
20. Robinson, B. S.; Rathjen, D. A.; Trout, N. A.; Easton, C.
J.; Ferrante, A. J. Immunol. 2003, 171, 4773.
21. Carter, G. W.; Young, P. R.; Albert, D. H.; Bouska, J.;
Dyer, R.; Bell, R. L.; Summers, J. B.; Brooks, D. W.
J. Pharmacol. Exp. Ther. 1991, 256, 929.
22. Zheng, M.-Y.; Zhang, ZH.-SH.; Zhu, W.-L.; Liu, H.; Luo,
X.-M.; Chen, K.-X.; Jiang, H.-L. Bioorg. Med. Chem.
2006, 14, 3428.
26. Charlier, C.; Henichart, J.-P.; Durant, F.; Wouters, J.
J. Med. Chem. 2006, 49, 186.
27. Morris, G. M.; Goodsell, D. S.; Huey, R.; Hart, W. E.;
Halliday, S.; Belew, R.; Olson, A. J. AutoDock Version
3.0.3 The Scripps Research Institute, Molecular Graph-
ics Laboratory, Department of Molecular Biology,
1999.
28. Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.;
Hart, W. E.; Belew, R. K.; Olson, A. J. J. Comput. Chem.
1998, 19, 1639.
29. Liu, H.; Huang, X.; Shen, J.; Luo, X.; Li, M.; Xiong, B.;
Chen, G.; Shen, J.; Yang, Y.; Jiang, H.; Chen, K. J. Med.
Chem. 2002, 45, 4816.
23. Altschul, S. F.; Gish, W.; Miller, W.; Myers, E. W.;
Lipman, D. J. J. Mol. Biol. 1990, 215, 403.