1436
P. Biju et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1434–1437
Table 3
(3,4-Diamino-1,2,5-thiadiazole): effect of right-side heteroaryl substituents R1 and left-side subtituent R on CXCR2 and CXCR1 binding versus IL-8
S
N
N
RI
R
N
N
H
H
Compound
R
R1
CXCR2 Kia (nM)
CXCR1 Kia (nM)
O
N
29
18
1270
O
O
O
OH
F3C
N
30
31
32
33
7.5
38
749
168
114
79
O
OH
F3C
N
O
O
OH
N
O
13
NC
O
O
OH
OH
OH
N
O
34
NC
NC
N
O
34
14
44
O
a
Values are reported as means of two experiments.
Table 4
In vitro hPMN MPO release for selected list of compounds
References and notes
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Compound
hPMN MPO release
10 nM IL-8 IC50 (nm)
hPMN MPO release
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a
a
100 nM GRO-
a
IC50 (nm)
24
25
3910
143
36
21
a
Values are reported as means of two experiments.
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Table 2 shows the effect of various right-side heteroaryl
amine modifications on both CXCR2 and CXCR1 inhibitory activ-
ities. In general, the furyl amine-substituted thiadiazoles showed
similar activity profiles to the right-side phenyl compounds.
Most of these compounds showed weaker binding affinity to-
wards the CXCR1 receptor with the exception of compound 25
that showed reasonable inhibitory activity towards both
receptors.
Table 3 summarizes our efforts to further improve both CXCR2
and CXCR1 receptor-binding affinities. Table 4 summarizes limited
functional data in in vitro human neutrophil (hPMN) MPO release
assay11 for compounds 24 and 25.
In summary, we have discovered a novel series of 3,4-diamino-
1,2,5-thiadiazoles as potent and selective CXCR2 receptor
antagonists.
Acknowledgments
We thank Dr. Robert Aslanian, Dr. Christopher Boyce, and Dr.
John Piwinski, from Schering-Plough Research Institute.