1974
M. Hieke et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1969–1975
Table 4
data Figure S5): Compounds 19, 28, 29 and 31 exhibit significantly
(p >0.95) higher potency in cell-free assay system than expected.
While the Boc carbamate group of compound 19 might be cleaved
in whole-cell system, compounds 28, 29 and 31 might accumulate
in cell membrane due to the high lipophilicity.
Influence of lipophilic backbone optimization on inhibition of 5-LO product formation
R1
5-LO product
formation IC50 (lM)
NH
In summary, we have developed a set of potent 5-LO inhibitors
characterized by a central imidazo[1,2-a]pyridine scaffold. Starting
with a preliminary screening of commercially available substances,
we investigated the SAR of broad structural modifications of the
imidazo[1,2-a]pyridine compounds. Thereby, we were able to iden-
tify a series of 5-LO inhibitors which are active in submicromolar
concentrations in intact cells and a cell-free system. Imidazo[1,
2-a]pyridines and related scaffolds were synthetically accessible
by means of multicomponent one-pot Groebke reaction. We
prepared a set of potent direct 5-LO inhibitors by systematic varia-
tion of the heterocyclic core, the core substituents and the phenyl
substituents. The most potent compounds show a five- to 10-fold
Compound
N
R2
N
R1
R2
PMNL
S100
26
27
28
29
30
31
OMe
OMe
OPh
H
H
OBn
H
OMe
H
OBn
OPh
H
1.22
1.3
0.5
0.28
0.26
0.43
0.43
0.72
0.05
0.03
0.08
0.04
higher inhibitory potency than zileuton (IC50 = 0.5–1 l
M11). This
of N-Boc-piperazine instead of the morpholine-ring (19) caused a
slight loss of activity (IC50 = 0.47 M). Due to synthetic difficulties
we were not able to obtain the deprotected derivative.
All tested derivatives of this sub-series were able to inhibit 5-LO
product formation in submicromolar ranges, although it remains to
be elucidated if these compounds show the same promising char-
acteristics as compound 14.
together with the promising molecular pharmacological profile in
mind (demonstrated with compound 1425) encourages us for
further investigations to develop novel effective anti-inflammatory
drugs based on this imidazo[1,2-a]pyridine scaffold.
l
Acknowledgment
Based on the potent morpholine moiety in part A, we focused on
the central imidazo[1,2-a]pyridine part and synthesized different
bicyclic scaffolds in part A (Table 3). Therefore, we introduced an
additional nitrogen resulting in imidazo[1,2-a]-pyrimidine (20), -
pyridazine (21), -pyrazine (22) and -thiazole (23) fused scaffolds,
respectively. In summary, introduction of any additional nitrogen
to the bicyclic scaffold led to at least four- to eight-fold decreased
The authors thank LOEWE Lipid Signaling Forschungszentrum
Frankfurt (LiFF), the Oncogenic Signaling Frankfurt (OSF), the EU
(LSHM-CT-2004-0050333) and Fonds der Chemischen Industrie
for financial support. E.B. thanks DAAD-La Caixa (Spain) for a
fellowship.
Supplementary data
activity (IC50 = 1.5–3.5
lM) compared to the imidazo[1,2-a]pyri-
dine scaffold in 17 (IC50 = 0.42
inhibitory potential of the morpholine derivatives.
Furthermore, two benzimidazole derivatives (24, 25) were syn-
thesized as analogs to compounds 13 and 15 which showed a two-
to seven-fold decrease of inhibitory activity (IC50 = 0.5 and 1.2 lM).
l
M) corroborating the promising
Supplementary data (synthetic conditions, 1H and 13C NMR-
data of intermediates and final compounds, mass spectrometry
and combustion analysis data of final compounds, assay systems)
associated with this article can be found, in the online version, at
Interestingly, both benzimidazole derivatives just weakly inhibited
5-LO product formation in the cell-free assay (IC50 >10 and
5.8 lM). Therefore we conclude that additional, indirect effects
References and notes
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