Tryptamine and homotryptamine-based sulfonamides as potent and selective inhibitors of 15-lipoxygenase

Article abstract of DOI:10.1016/j.bmcl.2004.12.081

A series of inhibitors of mammalian 15-lipoxygenase based on tryptamine and homotryptamine scaffolds is described. Compounds with aryl substituents at C-2 of the indole core of tryptamine and homotryptamine sulfonamides (e.g., 37a-p) proved to be potent i

Full text of DOI:10.1016/j.bmcl.2004.12.081

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1435–1440
Tryptamine and homotryptamine-based sulfonamides as potent
and selective inhibitors of 15-lipoxygenase
David S. Weinstein,* Wen Liu, Zhengxiang Gu, Charles Langevine, Khehyong Ngu,
Leena Fadnis, Donald W. Combs, Doree Sitkoff, Saleem Ahmad, Shaobin Zhuang,
Xing Chen, Feng-Lai Wang, Deborah A. Loughney, Karnail S. Atwal, Robert Zahler,
John E. Macor, Cort S. Madsen and Natesan Murugesan*
Bristol–Myers Squibb Pharmaceutical Research Institute, Bristol–Myers Squibb, PO Box 4000, Princeton, NJ 08543, USA
Received 17 November 2004; revised 23 December 2004; accepted 30 December 2004
Available online 22 January 2005
Abstract—A series of inhibitors of mammalian 15-lipoxygenase based on tryptamine and homotryptamine scaffolds is described.
Compounds with aryl substituents at C-2 of the indole core of tryptamine and homotryptamine sulfonamides (e.g., 37a–p) proved
to be potent inhibitors of the isolated enzyme. Selected compounds also demonstrated desirable inhibition selectivities over isozymes
5- and P-12-LO.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Mammalian lipoxygenases (LOÕs) are nonheme iron-
containing enzymes responsible for the oxidation of
polyunsaturated fatty acids and esters to hydroperoxy
derivatives.1 A heterogeneous family of enzymes distri-
buted widely throughout the plant and animal king-
doms,2 they are named according to the position at
which a key substrate, arachidonic acid (AA) is oxi-
dized. Of the mammalian lipoxygenases involved in
the etiology of human disease, 5-lipoxygenase (5-LO)
is now well established as a target for inhibiting the pro-
duction of leukotrienes involved in the progression of
inflammatory diseases, in particular asthma.3 More re-
cently, 15-lipoxygenase (15-LO) has emerged as an
attractive target for therapeutic intervention.4 15-LO
has been implicated in the progression of certain can-
cers5 and chronic obstructive pulmonary disease
(COPD).6 Evidence for the inhibition of 15-LO in the
treatment of vascular disease is, however, most compel-
ling.7 Both transgenic and knockout studies implicate a
role for 15-LO in atherogenesis.8 The enzyme is abun-
dantly expressed in macrophages residing within the
atherosclerotic lesion.4 In addition, the immediate prod-
ucts of 15-LO oxidation of AA and linoleic acid (LA)
have been shown to be pro-inflammatory9 and pro-
thrombotic.10
Previously reported inhibitors of 15-LO include PD-
146176 (1, Fig. 1),11 nordihydroguaiaretic acid (NDGA,
2),12 the sponge-derived terpenoids jaspaquinol (3) and
jaspic acid (4),13 and some naturally occurring flavo-
noids.14 PD-146176 reportedly demonstrated efficacy
in an animal model of atherosclerosis.11 At least some
of the inhibitory effects of these naturally-derived phe-
nol-containing 15-LO inhibitors 2–4 is believed to be
due to their anti-oxidant and/or radical scavenging
properties.12–15
We set out to identify potent inhibitors of 15-LO with
selectivity over the two other significant human lipoxy-
genases, 5-LO and platelet-derived 12-LO (P-12-LO).
To reduce the potential for off-target pharmacology,
the inhibitors would also need to be reversible, nonredox
inhibitors of the enzyme. A virtual 4-point pharmaca-
phore screen16 of our corporate compound collection
utilizing 1 was carried out, and high-scoring compounds
were assayed for their inhibition of isolated rabbit retic-
ulocyte 15-LO in the presence of both AA and LA as
substrates.17 These efforts led to the identification of
dansyl tryptamine 5 as a modestly potent 15-LO inhibi-
tor with an IC50 of 4.1 lM with LA as substrate.
Keywords: 15-Lipoxygenase inhibitors; Arachadonic acid; Linoleic
acid; Tryptamine; Homotryptamine; Sulfonamides.
*
Corresponding authors. Tel.: +1 609 252 3060; fax: +1 609 252 6804;
e-mail addresses: david.weinstein@bms.com; natesan.murugesan@
bms.com
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.12.081

1436
D. S. Weinstein et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1435–1440
Figure 1. Some known inhibitors of 15-LO and dansyl tryptamine 5. aEnzyme inhibition measured in the presence of LA as substrate. bStandard
deviations are based on multiple test occasions (n P 2). As reported in the literature.12,13
c
Replacement of the dansyl moiety of 5 with para-substi-
tuted phenyl sulfonamides (prepared by treatment of
tryptamine with commercially available sulfonyl chlo-
rides in dichloromethane in the presence of triethyl-
amine) gave compounds of improved potency (Table
1). While introduction of a methyl or ethyl group (6
and 7) provided inactive compounds, chain elongation
to n-propyl led to a compound (8) equipotent with dan-
syl tryptamine 5. Potency continued to improve with
chain extension, leading to the identification of the n-
pentyl substituted phenyl sulfonamide 10 as the first
submicromolar 15-LO inhibitor in this series.
Table 1. 15-LO inhibitory activities of tryptamine sulfonamides
Compd
R
15-LO IC50 (lM)
LAa
AAb
6
CH3
Et
>10
>10
>10
>10
7
8
n-Propyl
n-Butyl
3.13 0.05
3.07 2.22
0.42 0.01
3.40 2.0
0.92
3.2
4.0
The biaryl tryptamine sulfonamides 11–20 were pre-
pared via Suzuki-coupling of the 4-bromophenyl sulfon-
amide derivative 21 with arylboronic acids, as shown in
Scheme 1.
9
10
11
12
13
14
15
16
17
18
19
20
n-Pentyl
Ph
1.02 0.13
4.2
0.46
2-Me-Ph
3-Me-Ph
4-Me-Ph
4-Et-Ph
4-i-Pr-Ph
4-n-Butyl-Ph
4-i-Butyl-Ph
4-t-Bu-Ph
4-OMe-Ph
0.45
c
–
0.26
0.32 0.07
0.47
0.47
The biphenylsulfonamide derivative 11 was found to be
equipotent with dansyl tryptamine 5. A methyl walk on
the pendant phenyl ring gave improvement in activity at
all three positions (compounds 12–14), particularly in
competition with AA as substrate. para-Substitution of
the distal phenyl ring in 11 with small alkyl groups led
to improved activity against both AA and LA as sub-
strates (15–19). The isopropyl and the 4-tert-butyl
groups (compounds 16 and 19, respectively) at this posi-
tion were found to provide the most potency.
0.28 0.02
0.53
0.91
0.14 0.05
0.20
0.17
0.27
1.50
0.23
1.09
a Enzyme inhibition measured in the presence of linoleic acid as
substrate.
b Enzyme inhibition measured in the presence of arachidonic acid as
substrate.
c Not tested.
The linker region between indole and sulfonamide moi-
eties was then studied (Fig. 2, Table 2). N-Methylation
of the sulfonamide moiety of 10 gave 22, which showed
a complete loss of activity against 15-LO. The acidic
acylsulfonamide analogue 23 and racemic sulfonyl pyr-
rolidine 24 also proved to be inactive (IC50 >10 lM).
The a-methyl sulfonamide 25 led to a nearly fourfold

D. S. Weinstein et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1435–1440
1437
Scheme 1. Reagents and conditions: (a) ArB(OH)2, Na2CO3, ethanol/toluene (1:1), Pd(PPh3)4 (65–85%).
a
Figure 2. SAR of the linker group. Enzyme inhibition measured in the presence of LA as substrate.
To identify the optimal chain length between the indole
and the sulfonamide moieties, the homotryptamine sul-
fonamide derivative 26 was prepared (Table 2). This
compound proved to be 10-fold more potent than the
corresponding tryptamine derivative 10 with LA as sub-
strate, and about fourfold more potent with AA as sub-
strate. Further chain-length extension of the linker
portion proved to be deleterious, the indolylbutyl phe-
nylsulfonamide 27 losing two to threefold potency over
26.
Table 2. 15-LO inhibitory activities of tryptamine and homotrypt-
amine sulfonamides 26–34
Compd
n
R
15-LO IC50 (lM)
LAa
AAb
The effects of introduction of substituents to the benzene
ring of the indole core were then studied. Little change
in potency (with AA as substrate) was noted with the
introduction of methyl groups to C-7 and C-5 of the in-
dole core (28 and 29). Fluorine substituents at C-5 and
C-6 (30 and 31) also failed to improve potency. Intro-
duction of a carboxymethyl group to C-6 of the indole
core (32) did provide a twofold improvement in potency
over the parent tryptamine derivative 10, while the cor-
responding carboxylic acid 33 proved to be virtually
inactive.
26
10
27
28
29
30
31
32
33
34
2
1
3
1
1
1
1
1
1
1
H
0.047 0.003
0.42 0.01
0.11 0.02
0.30 0.11
1.02 0.13
0.73 0.09
3.3
H
H
c
7-CH3
5-CH3
5-F
—
—
3.9
6.3
—
—
6-F
2.9
6-CO2CH3
6-CO2H
5-(2-Pyrrolyl)
0.236
24
0.78 0.13
0.472 0.08
>30
—
a Enzyme inhibition measured in the presence of linoleic acid as
substrate.
b Enzyme inhibition measured in the presence of arachidonic acid as
substrate.
An important advance was realized with the incorpora-
tion of substituents to C-2 of the indole core (Scheme 2,
Table 3). Regioselective bromination of C-2 of phthal-
imide-protected tryptamine 35a was carried out as previ-
ously described,18 and was also found to be effective for
the bromination of homotryptamine phthalimide19 35b.
Subsequent Suzuki couplings of bromides 36a,b with
c Not tested.
loss in potency relative to the unsubstituted tryptamine
derivative 10.

1438
D. S. Weinstein et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1435–1440
Scheme 2. Reagents and conditions: (a) pyridinium tribromide, THF, CHCl3 (73%); (b) R1B(OH)2, LiCl, Na2CO3, ethanol/toluene (1:1), Pd(PPh3)4
(5 mol %) (30–75%); (c) NH2NH2, MeOH (80–95%); (d) p-(R2)PhSO2Cl, Et3N, CH2Cl2 (95%).
Table 3. 15-LO inhibitory activities of C-2 substituted tryptamine and homotryptamine sulfonamides 37a–p
Compd
n
R1
R2
15-LO IC50 (lM)
AAb
LAa
6
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
1
1
H
CH3
CH3
>10
0.11
>10
0.78
37a
37b
37c
37d
37e
37f
37g
37h
37i
(4-OCH3)Ph
(4-OCH3)Ph
(4-OCH3)Ph
(4-OCH3)Ph
(4-OCH3)Ph
Ph
c
n-Butyl
n-Pentyl
CO2H
0.11 0.01
0.037
>10
—
0.164
c
—
0.247
Ph
0.027 0.005
0.062
0.025
n-Pentyl
n-Pentyl
n-Pentyl
n-Pentyl
n-Pentyl
n-Pentyl
n-Pentyl
n-Pentyl
Ph
0.14 0.023
0.058 0.012
0.12 0.040
0.039
(3-CH3)Ph
(4-Cl)Ph
(4-OEt)Ph
0.032
0.011
0.011
37j
(4-CF3)Ph
0.042
0.132
37k
37l
(2,5-DiOMe)Ph
2-Benzofuranyl
2-Benzofuranyl
2-Benzofuranyl
2-Dibenzofuranyl
3-Quinolinyl
0.028 0.001
0.006 0.001
0.010 0.003
0.008 0.001
0.010 0.002
0.013
0.021 0.001
0.014
0.017
37m
37n
37o
37p
n-Pentyl
n-Pentyl
0.071 0.032
0.050
a Enzyme inhibition measured in the presence of linoleic acid as substrate.
b Enzyme inhibition measured in the presence of arachadonic acid as substrate.
c Not tested.
commercially available boronic acids followed by
hydrazinolysis of the phthalimide functionality and sulf-
onylation of the resulting primary amines gave C-2 aryl-
substituted tryptamine and homotryptamine sulfon-
amides 37a–p.
ities of 37l–n is noteworthy given the large difference in
potencies for the C-2 unsubstituted tryptamine and
homotryptamine derivatives 10 and 26. Groups of simi-
lar or even large size to benzofuran (dibenzofuran 37o
and quinoline 37p) were nearly equally tolerated as ben-
zofuran with LA as substrate, and 4–5 fold less potent
with AA as substrate.
While tosyl tryptamine 6 is inactive against 15-LO,
introduction of a p-methoxy phenyl group to C-2 of
the indole core gave a compound (37a) with greater than
100-fold improvement in potency. Chain elongation of
the alkyl group at the para-position of the phenyl sulfon-
amide moiety to n-butyl (37b) gave no improvement in
inhibition, while the n-pentyl analog 37c provided only
modest improvements in potency, obviating the need
for a very large hydrophobic substituent at that posi-
tion. Substitution with a carboxylic acid group provided
an inactive compound (37d). The biphenyl sulfonamide
37e proved to be of similar potency to n-pentyl substi-
tuted 37c. Little effect on potency was noted with mod-
ification of the substituents about the phenyl ring at C-2
of the indole core (37f–k). More dramatic effects were
observed with increasing bulk of the indole C-2 group.
Thus, the 2-benzofuranyl tryptamine and homotrypta-
mine derivatives 37l–m20 were both single digit nanomo-
lar enzyme inhibitors (LA), with very similar potencies
employing AA as substrate. The nearly equipotent activ-
Structure–activity relationships around the 2,20-linked
benzofuranyl tryptamine core of sulfonamide 37l were
then studied (Table 4). To this end, phthalimide 38
(Scheme 3) was prepared following the procedures
described in Scheme 2. Methylation of the free indole
nitrogen, followed by hydrazinolysis of the phthal-
imide and subsequent sulfonylation provided the N-
methyl tryptamine derivative 39. The amine resulting
from hydrazinolysis of phthalimide 38 was also sulfonyl-
ated with tosyl chloride to give 40a. Sulfonylation of the
same intermediate amine with p-bromobenzene sulfonyl
chloride gave bromide 40b, which was subsequently
coupled with 4-pyridyl boronic acid under standard
Suzuki conditions to give the 4-pyridylphenyl sulfon-
amide 40c. Amides 40d–j were also prepared by sulfonyl-
ation with 4-(chlorosulfonyl)benzoic acid followed by
condensation with various amines under standard
conditions.

D. S. Weinstein et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1435–1440
1439
Table 4. 15-LO inhibitory activities of 2-(20-benzofuranyl)tryptamine
sulfonamides 37l, 39, 40a–j
chains included acyl hydrazide 40h, alcohol 40i, and
amine 40j. The improved physicochemical properties
of these compounds was accompanied by some compro-
mise in inhibitory potency over the simply alkyl-substi-
tuted benzene sulfonamides 37l and 40a.
Compd
R
15-LO IC50 (lM)
LAa
AAb
37l
39
n-Pentyl
—
CH3
0.006
0.02
0.143 0.029 1.42
0.010 0.001 0.078
0.030 0.002 0.161
Several compounds were assayed for inhibition selectiv-
ities over the lipoxygenase isoforms 5- and P-12- LO
(Table 5). Inhibitory activities of potent 15-LO inhibi-
tors in these related enzymes were measured following
the oxidation of AA as substrate. All compounds tested
showed at least a 20-fold selectivity for 15-LO over 5-
LO. The homotryptamine-derived 4-(n-pentyl)benzene
sulfonamide 26 proved to be only modestly selective
(three-fold) for 15-LO over P-12-LO. The incorporation
of an aryl group to C-2 of the indole core of this series
appears to have ameliorated this problem, with com-
pounds 37c,f,h,l and 40a,h proving to be at least 60-fold
selective for 15-LO over P-12-LO.
40a
40b
40c
40d
40e
40f
40g
40h
40i
Br
4-Pyridyl
C(O)NHPh
C(O)NH(4-OCH3)Ph 0.011 0.001 0.026
0.047 0.01
0.179 0.113
0.015 0.003 0.051
C(O)NHn-butyl
C(O)NHcyclohexyl
C(O)NHNH2
C(O)N(CH3)-
(CH2)2OH
0.042 0.008 0.112
0.012 0.001 0.034
0.089 0.010 0.135 0.045
0.440 0.008 4.05
40j
C(O)N(CH3)-
(CH2)2N(CH3)2
0.076 0.011 0.382
a Enzyme inhibition measured in the presence of linoleic acid as
substrate.
b Enzyme inhibition measured in the presence of arachidonic acid as
substrate.
The identification of potent inhibitors of 15-LO may
ultimately lead to therapies for indications in which
the enzyme is believed to be involved. The work de-
scribed here has demonstrated that highly potent inhib-
itors of 15-LO may be generated via simple tryptamine
and homotryptamine precursors by introduction of aryl
The N-methyl indole analog 39 proved to be signifi-
cantly less potent than the corresponding unmethylated
indole 37l. The loss in potency may be attributed to size
restrictions imposed by the enzyme and/or the need for a
hydrogen bond donor at this position in the inhibitor.
The tosyl benzofuranyl tryptamine 40a maintained most
of the potency of the n-pentyl benzene sulfonamide 37l,
offering the advantage of somewhat decreased lipophil-
icity. The 4-pyridyl substituent of 40c gave no distinct
advantage over the simple methyl group of 40a, with a
fivefold decrease in potency in competition with LA as
substrate. Anilides 40d–e and secondary amides 40f–g
also maintained good enzyme inhibitory activity. Efforts
to improve the hydrophilicity (log P) of the benzofura-
nyl tryptamine leads with polar group-bearing side
Table 5. Selectivity data for selected compounds
Compd
IC50 (lM)
5-LO
P-12-LO
26
>10
8.9
>3
1.07
>10
>10
>10
>3
37c
37f
37h
37l
40a
40h
>3
>3
>10
3.5
>10
>10
Scheme 3. Reagents and conditions: (a) NaH, MeI, DMF (97%); (b) NH2NH2, MeOH (93–96%); (c) 4-n-pentylbenzenesulfonyl chloride,
triethylamine, CH2Cl2 (95%); (d) p-toluenesufonyl chloride, triethylamine, CH2Cl2 (95%); (e) (4-Br)PhSO2Cl, triethylamine, CH2Cl2 (95%); (f) 4-
pyridylboronic acid, LiCl, Na2CO3, ethanol/toluene (1:1), Pd(PPh3)4 (5 mol %) (38%); (g) 4-(chlorosulfonyl)benzoic acid, triethylamine, CH2Cl2
(85%); (h) amine, HOAt/EDC, CH3CN (55–75%).

1440
D. S. Weinstein et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1435–1440
14. (a) Sadik, C. D.; Sies, H.; Schewe, T. Biochem. Pharmacol.
2003, 65, 773; (b) Schewe, T.; Sadik, C.; Klotz, L. O.;
Yoshimoto, T.; Kuhn, H.; Sies, H. Biol. Chem. 2001, 382,
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15. Kemal, C.; Louis-Flamberg, P.; Krupinski-Olsen, R.;
Shorter, A. L. Biochemistry 1987, 26, 7064.
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Hulme, C.; Labaudiniere, R. F. J. Med. Chem. 1999, 42,
3251.
and heteroaryl substituents to the indole C-2 position.
Similarly, a wide range of substituents are tolerated on
the aryl sulfonamide portion of the molecule, and pro-
vide a handle for modulating their physical properties.
The unprecedented potency and lipoxygenase selectivity
profiles of the tryptamine sulfonamides make them
attractive leads for optimization of pharmacokinetic
properties and assessment in models of 15-LO mediated
diseases, such as atherosclerosis.
17. 15-LO enzyme was obtained from phenylhydrazine-
treated rabbits and purified according to the method of
Rapoport et al. [Eur. J. Biochem. 1979, 96, 546].
Recombinant human 5-LO and 12-LO enzymes were
from a commercial source (Caymen Chemical). The
inhibitory activity of the compounds against purified 15-
LO enzyme was determined using a standard colorimetric
assay in which the lipid hydroperoxide product of either
linoleic or arachidonic acid [13-hydroperoxyoctadecadi-
enoic acid (13-HPODE) and 15-hydroperoxyeicosatetra-
enoic acid (15-HPETE), respectively] oxidizes Fe2+ under
mildly acidic conditions Jiang et al. [Lipids 1991, 26, 853].
The Fe3+ forms a chromophore with xylenol orange that
absorbs strongly at 560 nm. Inhibitory activity was
compared to an uninhibited (maximal) reaction to yield
% inhibition (compound concentration in which enzyme
activity is reduced by 50% is termed the IC50). The
inhibitory activity of the compounds against 5-LO [Bio-
chemistry 1995, 34, 13603] and 12-LO [Methods Enzymol.
1982, 86, 49] enzyme were determined by standard
methods using a spectrophotometer to measure the rate
of diene formation (A234). Many of the IC50 values
generated for 15-LO enzyme using the colorimetric assay
were also verified in the spectrophotometric assay.
18. Chu, L.; Fisher, M. H.; Goulet, M. T.; Wyvratt, M. J.
Tetrahedron Lett. 1997, 38, 3871.
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20. N-(2-(2-(benzofuran-2-yl)-1H-indol-3-yl)ethyl)-4-pentyl-
benzenesulfonamide (37l). HPLC [YMC S5 ODS
4.6 · 40 mm, 4 mL/min, 90% water/methanol to 90%
methanol/water, 0.2% phosphoric acid, 4 min gradient]
tR = 4.28 min. 1H NMR (400 MHz, CDCl3): d 0.80 (t, 3H,
J = 7 Hz), 1.20–1.27 (m, 4H), 1.49 (m, 2H), 2.51 (dd, 2H,
J = 15, 8 Hz), 3.22 (dd, 2H, J = 13, 6 Hz), 3.29 (dd, 2H,
J = 13, 7 Hz), 6.93 (s, 1H), 7.04 (dd, 1H, J = 15, 8 Hz),
7.10 (d, 2H, J = 8 Hz), 7.15–7.26 (m, 3H), 7.31 (d, 1H,
J = 8 Hz), 7.42 (d, 2H, J = 8 Hz), 7.53 (d, 1H, J = 7 Hz),
7.57 (d, 2H, J = 8 Hz), 8.54 (s, 1H). 13C NMR (100 MHz,
CDCl3): d 14.36, 22.83, 25.97, 31.08, 31.76, 36.15, 43.33,
103.21, 111.24, 111.36, 111.54, 119.21, 120.77, 121.53,
123.81, 124.04, 125.05, 126.05, 127.38, 128.98, 129.35,
136.26, 137.36, 148.62, 148.82, 154.45. ESI-MS m/e Calcd
for C29H30N2O3S 486.2. Found 487.4 [M+H]+.
13. Carroll, J.; Johnsson, E. N.; Ebel, R.; Hartman, M. S.;
Holman, T. R.; Crews, P. J. Org. Chem. 2001, 66, 6847.