3,4-Diamino-2,5-thiadiazole-1-oxides as potent CXCR2/CXCR1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2007.10.094

A series of novel and potent 3,4-diamino-2,5-thiadiazole-1-oxides were prepared and found to show excellent binding affinities for CXCR2 and CXCR1 receptors and excellent inhibitory activity of Gro-α and IL-8 mediated in vitro hPMN MPO release of CXCR2 an

Full text of DOI:10.1016/j.bmcl.2007.10.094

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 228–231
3,4-Diamino-2,5-thiadiazole-1-oxides as potent
CXCR2/CXCR1 antagonists
Purakkattle Biju,a,* Arthur Taveras,a, Younong Yu,a Junying Zheng,a Jianhua Chao,a
Diane Rindgen,a James Jakway,a R. William Hipkin,a James Fossetta,a Xuedong Fan,a
Jay Fine,a Hongchen Qiu,a J. Robert Merrittb and John J. Baldwinb
aSchering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
bPharmacopeia Drug Discovery, Inc., 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA
Received 26 September 2007; revised 23 October 2007; accepted 25 October 2007
Available online 30 October 2007
Abstract—A series of novel and potent 3,4-diamino-2,5-thiadiazole-1-oxides were prepared and found to show excellent binding
affinities for CXCR2 and CXCR1 receptors and excellent inhibitory activity of Gro-a and IL-8 mediated in vitro hPMN MPO
release of CXCR2 and CXCR1 expressing cell lines. On the other hand, a closely related 3,4-diamino-2,5-thiadiazole-dioxide did
not show functional activity despite its excellent binding affinities for CXCR2 and CXCR1 in membrane binding assays. A detailed
SAR has been discussed in these two closely related structures.
Ó 2007 Elsevier Ltd. All rights reserved.
Chemokines1 are chemotactic cytokines that are re-
leased by a wide variety of cells to attract macrophages,
T-cells, eosinophils, basophils, neutrophils and endothe-
lial cells to sites of inflammation and tumour growth. In
general, chemokines have been classified2 into two main
classes, the CXC-chemokines and the CC-chemokines.
The CXC-chemokines include interleukin-8 (IL-8), neu-
trophil activating protein-1(NAP-1), NAP-2, GRO-a
and many more. These CXC-chemokines3 promote the
accumulation and activation of neutrophils and hence,
they have been implicated in a wide range of acute
and chronic inflammatory disorders4 including psoriasis,
RA and COPD. IL-8 mainly activates neutrophils
through their G-protein coupled receptors, CXCR1
and CXCR2. Due to the obvious relationship between
IL-8 and inflammatory diseases, CXCR1 and CXCR2
antagonists5 are targets of small molecule drug discov-
ery. Several literature reports are available for the dis-
covery of CXCR2 antagonists.6
We have previously reported6 several 3,4-diaminocyclo-
but-3-ene-1,2-diones (e.g. 1) as potent CXCR2/CXCR1
antagonists. We envisaged that 2,5-thiadiazole-1-oxides
could be a viable replacement for the less known phar-
macophore cyclobutenedione. Several literature reports7
are available for the use of thiadiazole oxides in drug
discovery. Herein, we would like to disclose the medici-
nal chemistry efforts in replacing the centre pharmaco-
phore cyclobutenedione with 2,5-thiadiazole-1-oxides
and its structure–activity relationships with various right
side alkyl, aryl and heteroaryl motifs (R) as in structures
2 and 3.
O
S
n
O
O
N
N
N
O
N
R
N
N
H
N
N
H
H
OH
H
O
OH
O
2; n=1
3; n=2
1
The preparation of the 3,4-diaminothiadiazole dioxides
of general structure 3 was commenced with the readily
available 3,4-diethoxy-2,5-thiadiazoledioxide 4. A stan-
dard procedure for the synthesis of the left side pheno-
lic-aniline and the right side amines was described in
our previous publications.6 Coupling of the phenolic
amine 5 with the 3,4-diethoxythiadiazoledioxide 4
in ethanol afforded the intermediate 6, which upon
Keywords: CXCR2 and CXCR1 receptor; Thiadiazole-1-oxide;
Antagonist.
*
Corresponding author. Tel.: +1 908 740 3127; fax: +1 908 740
7152; e-mail: purakkattle.biju@spcorp.com
Present address: Alantos Pharmaceuticals, 840 Memorial Drive,
Cambridge, MA 02139, USA.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.10.094

P. Biju et al. / Bioorg. Med. Chem. Lett. 18 (2008) 228–231
229
O O
S
Table 1. (3,4-diamino-2,5-thiadiazole-1,1-dioxides): Effect of right side
substituents R on CXCR2 and CXCR1 binding versus IL-8
O O
S
N
N
N
N
N
i
N
NH2
N
OC2H5
O O
S
C2H5O OC2H5
O OH
H
OH
O
4
N
N
5
6
N
R
N
N
ii
H
O OH
H
NH2
7
O O
S
Compound
R
CXCR2 Kia
(nM)
CXCR1 Kia
(nM)
N
N
N
N
N
H
OH
O
H
8
8
NT
24
9
8990
2000
2800
652
Scheme 1. Reagents and conditions: (i) diisopropylethylamine,
CH3OH, rt, 6 h, 90%; (ii) CH3OH, diisopropylethyl amine, rt, 12 h,
80%.
O
O
9
10
11
subsequent treatment with commercially available
amine 7 or prepared amines resulted in the final prod-
ucts (8–17) in excellent yield, as depicted in Scheme 1.
We kept the left side phenolic amine 5 constant through-
out our studies and explored the SAR with right side
amines. Both aryl and heteroaryl substitutions were tol-
erated on the right side. Alkyl compounds were not as
potent as the aryl substituted ones. Binding affinities6
for compounds 8–17 are shown in Table 1. Compounds
12 and 15 showed excellent binding affinity for both
CXCR2 and CXCR1 receptors.
O
N
F
11
12
13
14
15
16
4.7
NT
184
11
46
5950
1100
61
O
O
After identifying a series of potent compounds in the
membrane binding assays, in vitro cell based functional
activity was determined in a human neutrophil (hPMN)
MPO release assay8 in the presence of various chemo-
attractants (IL-8 or GRO-a). We were surprised to no-
tice that none of these compounds exhibited functional
activity in in vitro cell based assays. The functional data
are shown in Table 2. The blood levels in rats following
oral administration were determined according to a ra-
pid rat pharmacokinetic screen.
O
O
O
O
O
Due to the unexpected lack of functional activity, efforts
were further focused on the modification of thiadiazole-
oxide centre core. We decided to follow up a structurally
closely related 3,4-diamino-2,5-thiadiazole-1-oxide9 2.
Following a similar procedure, coupling of the phenolic
aniline 5 with 3,4-diethoxy-2,5-thiadiazole-1-oxide 4a in
methanol afforded 6a, which upon subsequent treatment
with commercially available or prepared amines like 7a,
resulted in the final products (18–28) in excellent yield as
depicted in Scheme 2 and Table 3.
16
188
17
9
129
Cl
NT, not tested.
a Values are reported as the means of two experiments.
3,4-Diamino-2,5-thiadiazole-1-oxides (18–28) showed
excellent binding affinities for the CXCR2 receptor irre-
spective of the nature of right side substitution. In gen-
eral, compounds with a bulky substitution, like an
isopropyl or tert-butyl, showed better affinity towards
the CXCR1 receptor. After exploring a detailed SAR
with the right side amines, compound 27, with a tert-bu-
tyl side chain containing furan, showed excellent binding
affinity towards both the receptors. Moreover, com-
pounds 18 and 25 showed excellent blood levels in the
rapid rat pharmacokinetic screen. Unlike the thiadiazol-
edioxide 3 series, this series of compounds showed excel-
Table 2. In vitro hPMN MPO release and rapid rat pharmacokinetic
results for selected list of compounds
Compound hPMN MPO
release-10 nM
hPMN MPO
release 100 nM
r rat pK
(po) (lM h)
IL-8 IC50 (lM) GRO-a IC50 (lM)
8
9
8.99
NT
NT
NT
NT
À39% at 1
À12% at I
À11% at 1
3% at 1
2.3
1.87
14
15
16
À19% at 1
NT, not tested.

230
P. Biju et al. / Bioorg. Med. Chem. Lett. 18 (2008) 228–231
Table 4. In vitro hPMN MPO release and rapid rat pharmacokinetic
results for selected list of compounds
O
S
O
S
N
N
N
N
N
i
NH2
N
Compound hPMN MPO
release 10 nM
hPMN MPO
release, 100 nM
r rat pK
(po) (lM h)
N
C2H5O OC2H5
OC2H5
6a
O
OH
5
H
OH
O
4a
IL-8 IC50 (lM) GRO-a IC50 (lM)
ii
18
20
22
23
24
25
26
27
28
0.684
NT
0.038
0.331
0.028
0.133
0.008
0.013
0.132
0.008
0.027
5.28
119
O
NH2
O
S
7a
0.142
0.539
0.015
0.054
0.400
0.020
0.080
N
N
N
O
N
N
H
OH
O
H
23
Scheme 2. Reagents and conditions: (i) diisopropylethylamine, CH3OH,
rt, 10 h, 90%; (ii) CH3OH, diisopropylethyl amine, rt, 12 h, 80%.
NT, not tested.
Table 3. (3,4-Diamino-2,5-thiadiazole-1-oxides): Effect of right side
substituents R on CXCR2 and CXCR1 binding versus IL-8
lent functional activity in in vitro human neutrophil
(hPMN) MPO release assay8 (Table 4). Compounds 24
and 27 were identified as the most potent compounds
in the hPMN MPO release assay.
O
S
N
N
N
R
N
N
H
OH
H
O
In summary, we have discovered a novel series of potent
3,4-diamino-2,5-thiadiazole-1-oxides as CXCR2/CXCR1
receptor antagonists.
Compound
R
CXCR2 Kia
(nM)
CXCR1 Kia
(nM)
18
58
484
Acknowledgments
O
We thank Dr. Christopher Boyce, Dr. Robert Aslanian
and Dr. John Piwinski from Schering-Plough Research
Institute.
19
20
15
5
10000
1220
O
References and notes
21
22
23
24
F
8
4
3
9
4010
130
234
61
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