Unexpected reaction of 2-alkylsulfanylimidazoles to imidazol-2-ones: Pyridinylimidazol-2-ones as novel potent P38α mitogen-activated protein kinase inhibitors

Article abstract of DOI:10.1021/jm100161q

While optimizing the synthesis of 2-alkylsulfanyl-5-(2-aminopyridin-4-yl) imidazoles, we identified an unexpected reaction to pyridinylimidazol-2-ones. 2-Alkylsulfanylimidazoles, bearing a 2-hydroxyethyl or a 2,3-dihydroxypropyl moiety at the imidazole C2-S position, were converted by heating into imidazol-2-ones. These imidazol-2-ones were tested for their ability to inhibit p38α MAP kinase and LPS-stimulated TNF-α release in HWB. Introduction of an amino moiety at the pyridine C2 position led to compounds showing potent enzyme inhibitory activity with double-digit nanomolar IC ₅₀ values (5a: IC₅₀ = 23 nM).

Full text of DOI:10.1021/jm100161q

4798 J. Med. Chem. 2010, 53, 4798–4802
DOI: 10.1021/jm100161q
Unexpected Reaction of 2-Alkylsulfanylimidazoles to Imidazol-2-ones: Pyridinylimidazol-2-ones as
Novel Potent p38r Mitogen-Activated Protein Kinase Inhibitors
Pierre Koch and Stefan Laufer*
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls University of Tu€bingen,
Auf der Morgenstelle 8, 72076 Tu€bingen, Germany
Received February 5, 2010
While optimizing the synthesis of 2-alkylsulfanyl-5-(2-aminopyridin-4-yl)imidazoles, we identified an un-
expected reaction to pyridinylimidazol-2-ones. 2-Alkylsulfanylimidazoles, bearing a 2-hydroxyethyl or a 2,3-
dihydroxypropyl moiety at the imidazole C2-S position, were converted by heating into imidazol-2-ones.
These imidazol-2-ones were tested for their ability to inhibit p38R MAP kinase and LPS-stimulated TNF-R
release in HWB. Introduction of an amino moiety at the pyridine C2 position led to compounds showing
potent enzyme inhibitory activity with double-digit nanomolar IC50 values (5a: IC50 =23 nM).
Introduction
Imidazole derivatives display a wide range of biological acti-
vities asexemplified bythe amino acidhistidine. Manytri- and
tetrasubstituted pyridinylimidazoles, derived from the early
lead SKF86002,1 have been investigated as potent adenosine
triphosphate (ATPa) competitive inhibitors of p38R MAP
kinase, e.g., the prototype inhibitor SB2035802 or the recently
reported 2-alkylsulfanyl-4-(4-fluorophenyl)-5-(2-aminopyridin-
4-yl)-substituted imidazoles 1 (Figure 1).3-5 The p38R mitogen-
activated protein(MAP) kinase, a serine/threoninekinase, isa
key component of the cascade leading to proinflammatory
cytokines like tumor necrosis factor-R (TNF-R) and inter-
leukin-1β.6 Inhibition of p38RMAP kinase is therefore a promis-
ing therapeutic strategy for the treatment of cytokine driven
disorders.
Figure 1. Vicinal 4-fluorophenyl/pyridin-4-yl-substituted imidazoles
under investigation for p38R MAP kinase inhibition derived from
the early lead SKF86002.
The synthesis of the trisubstituted imidazole derivatives
1 bearing a polar moiety at the imidazole C2-S position (R2)
was published recently.5 Imidazoles 1 were prepared starting
from N-boc protected 2-amino-4-methylpyridine or 2-bromo-
4-methylpyridine in six or seven steps. The limitation of this
synthetic strategy is the introduction of the amino moiety (R1)
in the first step of the synthesis, which requires the addition
and removal of a protecting group.
To overcome this drawback, we developed another syn-
thetic strategy to 1 in which variable moieties R1 and R2 were
introduced in the last two steps of the synthesis (Scheme 1).
The key compound for this route was 4-(4-fluorophenyl)-5-(2-
fluoropyridin-4-yl)-1,3-dihydroimidazole-2-thione (2), which
was prepared in four steps starting from 2-fluoro-4-methyl-
pyridine.7 The alkylsulfanyl moiety (R2) was introduced by
nucleophilic substitution of thione 2 and the appropriate alkyl
halide. In the last step, the fluorine atom of 3 was displaced by
a primary amine 4 to obtain the imidazole derivative 1.
The reaction to (1R,4R)-4-{4-[4-(4-fluorophenyl)-2-(2-hydro-
xyethylthio)-1H-imidazol-5-yl]pyridin-2-ylamino}cyclohexanol
(1a) using this synthetic strategy was published recently
(Scheme 2).4 Thione 2 was treated under basic conditions with
2-bromoethanol to obtain 2-[4-(4-fluorophenyl)-5-(2-fluoro-
pyridin-4-yl)-1H-imidazol-2-ylthio]ethanol (3a). Finally, the
fluorine atom of 3a was displaced under microwave condi-
tions using an excess (8 equiv) of trans-4-aminocyclohexanol
(4a) to yield imidazole derivative 1a.
To extend this strategy to the synthesis of different sub-
stituted imidazole derivatives 1, we observed an unexpected
reaction, the conversion of 2-alkylsulfanylimidazoles bear-
ing a 2-hydroxyethyl or a 2,3-dihydroxypropyl moiety at the
imidazole C2-S position (Figure 1, R2) to imidazol-2-ones.
Results and Discussion
Chemistry. Compound 3b was prepared from thione 2 and
3-bromopropane-1,2-diol under basic conditions (Scheme 3).
The reaction of imidazole derivative 3b and primary amine
4a under the same conditions as for reaction of 3a and 4a
depicted in Scheme 2 (135 °C, 250 W) yielded two products.
In addition to the formation of the desired product (imida-
zole derivative 1b), 5a was identified (Scheme 3). Compound
5a bears the amino function at the pyridine C2 position, but
the sulfur moiety at the imidazole C2 position was exchanged
by an oxygen atom. This reaction was monitored via HPLC
(Table 1). After 2 h, the starting material 3b was consumed.
The imidazol-2-one derivative 5a accumulates with increasing
*To whom correspondence should be addressed. Phone: þ497071-
2972459. Fax: þ497071-295037. E-mail: stefan.laufer@uni-tuebingen.de.
a Abbreviations: ATP, adenosine triphosphate; MAP, mitogen-activated
protein; LPS, lipopolysaccharide; SEM, standard error of the mean; TNF-R,
tumor necrosis factor R; HWB, human whole blood.
r
pubs.acs.org/jmc
Published on Web 05/20/2010
2010 American Chemical Society

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 12 4799
Scheme 1. Retrosynthetic View of an Alternative Synthetic Strategy to Imidazole Derivative 1
Scheme 2. Nucleophilic Aromatic Substitution of 3a and 4aa
a Reagents and conditions: (i) 2-bromoethanol, sodium ethoxide, methanol, 4 h, room temp; (ii) 135 °C, 250 W, microwave irradiation.
Scheme 3. Nucleophilic Aromatic Substitution of 3b and 4aa
a Reagents and conditions: (i) 3-bromopropane-1,2-diol, sodium ethoxide, methanol, 16 h, room temp; (ii) 135 °C, 250 W, microwave irradiation.
Table 1. Reaction of 3b and 4a: Quantitation of Reactants and Products
by HPLCa (Microwave Conditions, 250 W, 135 °C)
The formation of the imidazol-2-one compound was not ob-
served by the reaction of imidazoles bearing an S-methyl, S-ethyl,
or S-benzyl moiety at the imidazole C2 position (Scheme 5),7,8
but rather, the formation of the imidazol-2-one depends on
the presence of hydroxy function(s) of the S-alkyl moiety.
A possible mechanism for the conversion of 2-alkylsulfa-
nylimidazoles bearing a 2-hydroxyethyl or a 2,3-dihydro-
xypropyl moiety at the imidazole C2-S position into imi-
dazol-2-ones is presented in Scheme6 (exemplifiedby reaction
of 3a and primary amine 4). After the nucleophilic aromatic
displacement of the fluorine atom at the pyridine moiety of
3a has taken place, the hydroxyethyl moiety at the imidazole
C2-S position of the alkylsulfanylimidazole 1 could react
intramolecularly to the 1,3-oxathiolane 9. Compound 9 will
finally be directly converted (maybe by hydrolysis) into the
thermodynamically more stable imidazol-2-one 5.
time, h
3b, %
1b, %
5a, %
0
1
2
4
100
21
0
0
59
18
1
0
17
75
91
0
a For HPLC conditions, see General in the Experimental Section.
reaction time, with the intermediate 2-alkylsulfanylimda-
zole compound 1b being converted into the imidazol-2-one
compound 5a.
In a variation of this reaction, 3a, bearing a hydroxyethyl
moiety at the imidazole C2-S position, was reacted with
3-methylbut-2-ylamine (4b) (Scheme 4). This reaction was mon-
itored via HPLC (Table 2). Formation of the imidazol-2-one
compound 5b occurred at a slower rate compared to the reaction
to the imidazol-2-one compound 5a monitored in Table 1.
The progress of the reaction was temperature dependent
(Table 2). Decreasing the reaction temperature to 110 °C
provided only 3% of the desired imidazole 1c, and none of the
imidazol-2-one 5b was formed. Increasing the reaction tempera-
ture to 160 °C resulted in a faster conversion of 1c and 5b. HPLC
studies indicated that the first reaction to occur was the nucleo-
philic aromatic substitution to afford the 2-alkylsulfanylimida-
zole 1c, which reached a maximum by 4 h. After that point, the
conversion of 1c to the imidazol-2-one 5b was the predominant
reaction. By 6 h, 36% of 1c and 28% of 5b had been formed.
After 10 h, the 2-alkylsulfanylimidazole 1c was converted
completely into the imidazol-2-one compound 5b (Table 2).
This unexpected reaction was used to synthesize additional
imidazol-2-ones 5c-e (Scheme 7). Imidazol-2-one 5c was pre-
pared by heating 3b and 1-phenylethylamine (4c) under reflux
conditions. Imidazol-2-ones 5d and 5e were synthesized by heat-
ing 3a and amine 4d or 4e in a sealed glass tube at 160 °C for 10 h.
To evaluate the influence of the pyridine-C2-amino moiety
on biological activity, we attempted to prepare 5f, which
lacked a substituent at this position (Scheme 8). 2-Bromo-
2-(4-fluorophenyl)-1-(pyridin-4-yl)ethanone hydrobromide
was reacted with urea in a microwave reactor. X-ray analysis
of the product9 showed that the oxazole 6 was formed and
not the desired imidazol-2-one 5f.
Another synthetic strategy toward imidazol-2-one 5f start-
ing from 2-(2-bromopyridin-4-yl)-1-(4-fluorophenyl)ethanone

4800 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 12
Scheme 4. Nucleophilic Aromatic Substitution of 3a and 4ba
Koch and Laufer
a Conditions: (i) 135 °C, 250 W, microwave irradiation.
Table 2. Reaction of 3a and 4b: Quantitation of Reactants and Products
by HPLCa (Microwave Conditions, 250 W, 135 °C, 110 °C, and 160 °C)
Scheme 5. Nucleophilic Aromatic Substitution of Imidazoles
Bearing an S-Methyl, S-Ethyl, or S-Benzyl Moiety at the Imida-
zole C2 Position and Different Amines
time, h
3a, %
1c, %
5b, %
135 °C
0
1
3
5
100
91
0
6
0
0.2
2
74
51
16
25
6
110 °C
160 °C
0
1
2
4
100
99
0
1
2
3
0
0
0
0
Scheme 6. Possible Mechanism for the Conversion of 2-Alkyl-
sulfanylimidazoles Bearing a 2-Hydroxyethyl Moiety at the
Imidazole C2-S Position into Imidazol-2-ones 5
98
97
0
1
100
79
61
45
29
0
0
17
31
37
36
0
0
2
2
2
4
16
28
89
6
10
a For HPLC conditions, see general part of the experimental section.
is depicted in Scheme 9. The bromosubstituted derivative 7
smoothly underwent a hydrogenolytic cleavage, yielding pure
unsubstituted pyridine 8. By use of an adaption of the Marck-
wald synthesis, R-aminoketone 8 was treated with potassium
cyanate to yield 4-(4-fluorophenyl)-5-(pyridin-4-yl)-1,3-dihy-
droimidazol-2-one (5f).
Biological Data. The inhibitory potencies of the title com-
pounds were evaluated using an isolated p38RMAP kinase assay,
wherein pyridinylimidazole SB203580 was used as a reference.10
The LPS-stimulated TNF-R release was tested using a human
whole blood (HWB) assay (see Supporting Information).
The 4(5)-aryl-5(4)-heteroaryl-substituted imidazolones
5a,d-f were potent inhibitors of p38R MAP kinase (Table 3).
Introduction of an amino moiety at the pyridine C2 posi-
tion (5a,d,e) increased the inhibitory activity and led to
IC50s in the isolated p38R MAP kinase assay in the low
double-digit nanomolar range. Imidazol-2-one 5a, bearing a
4-hydroxycyclohexylamino moiety at the pyridine C2 posi-
tion, was 20 times more potent than the pyridine-C2-unsub-
stituted derivative 5f. The release of LPS-stimulated TNF-R
from HWB was inhibited by the target compounds at con-
centrations in the low to submicromolar range (Table 3).
Compound 5a exhibited an IC50 similar to that of the
reference compound SB203580 with respect to the LPS-
stimulated TNF-R release, while 5d showed a clear, ∼4ꢀ
improvement in inhibitory potency compared to SB203580.
Compound 5d was docked into the ATP binding site of p38R
MAP kinase (Figure 2). The binding mode of the imidazol-
2-ones 5 is essentially identical to the binding mode of the
imidazole compound SB203580 except for the direct imidazole
N3-Lys53 hydrogen bond interaction.11 The 4-fluorophenyl
ring binds to the hydrophobic region I (selectivity pocket),
which is mediated by the presence of the gatekeeper residue
Thr106 in the ATP-binding site of p38R MAP kinase. The
nitrogen of the pyridin-4-yl moiety forms a crucial hydrogen
bond to the backbone NH of Met109 in the hinge region. In
addition to the binding mode of SB203580, the amino function
at the pyridine C2 position interacts with the carbonyl function
of Met109 via a hydrogen bond and the 3-methylbut-2-yl
moiety of 5d is situated in the hydrophobic region II.
Conclusion
Under elevated temperature, we observed the unexpec-
ted transformation of 2-alkylsulfanylimidazoles, bearing a
2-hydroxyethyl or a 2,3-dihydroxypropyl moiety at the imida-
zole C2-S position, into imidazol-2-ones.
These imidazol-2-ones were identified as novel potent inhibi-
tors of p38R MAP kinase with IC50 values down to the low
double-digit nanomolar range. Introduction of an amino func-
tion at the pyridine C2 position results in an increase of

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 12 4801
Scheme 7. Synthesis of 4-(4-Fluorophenyl)-5-(2-aminopyridin-4-yl)imidazol-2-ones 5c-ea
a Reagents and conditions: (i) reflux temperature, 7 h; (ii) 160 °C, 10 h, sealed tube.
4-(4-Fluorophenyl)-5-[2-(1-phenylethylamino)pyridin-4-yl]-1,3-
Scheme 8. Ring Closing Reaction of 2-Bromo-2-(4-fluorophenyl)-
1-(pyridin-4-yl)ethanone Hydrobromide and Ureaa
dihydroimidazol-2-one (5c). Compound 3b (0.54 g, 1.5 mmol)
and 1-phenylethylamine (1.81 g, 15 mmol) were heated for 7 h to
reflux temperature. After cooling to room temperature the mixture
was treated with an aqueous solution of citric acid (10%), which had
been brought to pH 5 with an aqueous solution of NaOH (20%).
The emulsion was extracted with ethyl acetate (3ꢀ). The combined
organic extracts were washed with citric acid (10%, pH 5), an
aqueous solution of Na2CO3 (10%), and saturated brine, dried over
Na2SO4, and concentrated in vacuo. The crude brown oily residue
was treated with diethyl ether, and a yellow precipitate was formed
which was filtered and dried. Yield 0.14 g (25%); C22H19FN4O (Mr
=374.41); 1H NMR (DMSO-d6) δ 1.35 (d, J=6.9 Hz, 3H, CH3),
4.79-4.86 (m, 1H, CH), 6.28-6.32 (m, 2H, C3/C5-H Pyr), 6.95 (d,
J=7.9 Hz, 1H, NH), 7.13-7.27 (m, 7H, C6H5, C3/C5-H 4-F-Phe),
7.32-7.40 (m, 2H, C2/C6-H 4-F-Phe), 7.78 (d, J=5.4 Hz, 1H, C6-H
Pyr), 10.50 (bs, 1H, NH), 10.58 (bs, 1H, NH); ESI-HRMS calcd,
C22H20FN4O [M þ H]þ 375.1616, obsd 375.1617.
a Reagents and conditions: (i) DMF, 135 °C, 250 W, microwave
irradiation.
(S )-4-(4-Fluorophenyl)-5-[2-(3-methylbutan-2-ylamino)pyridin-
4-yl]-1,3-dihydroimidazol-2-one (5d). Compound 3a (0.25 g, 0.75
mmol) and (S )-3-methylbutyl-2-amine (0.52 g, 6.0 mmol) were
stirred in a sealed glass tube for 10 h at 160 °C. After the mixture
was cooled to room temperature, the solvent was removed and the
residue was purified by flash chromatography (SiO2, DCM/
EtOH, 95:5 to 8:2) to afford 79 mg (31%) of a yellow solid.
C19H21FN4O (Mr = 340.39); [R]2D0 -21.2° (c 0.90, methanol); 1H
NMR (DMSO-d6) δ 0.79-0.84 (m, 6H, 2ꢀCH3), 0.96 (d, J=6.4
Hz, 3H, CH3), 1.61-1.75 (m, 1H, CH), 3.48-3.63 (m, 1H, CH),
6.20 (d, J=8.2 Hz, 1H, NH), 6.26 (d, J=5.5 Hz, 1H, C5-H Pyr),
6.32 (s, 1H, C3-H Pyr), 7.15-7.24 (m, 2H, C3/C5-H 4-F-Phe),
7.35-7.42 (m, 2H, C2/C6-H 4-F-Phe), 7.79 (d, J = 5.4 Hz, 1H,
C6-H Pyr), 10.52 (m, 2H, 2x NH); ESI-HRMS calcd,
C19H22FN4O [M þ H]þ 341.1772, obsd 341.1773.
inhibitory activity caused, on the one hand, by an additional
hydrogen bond interaction to the hinge region and, on the other
hand, by interaction possibilities with the hydrophobic region II.
Experimental Section
General. All commercially available reagents and solvents
were used without further purification. The microwave reac-
tions were performed on a CEM Discover system. The optical
rotation data were obtained on a Perkin-Elmer polarimeter
model 241 (589 nm). NMR data were recorded on a Bruker
Spectrospin AC 200 at ambient temperature. Chemical shifts are
reported in ppm relative to the solvent resonance. High-resolu-
tion spectra (FT-ICR) were obtained on a Bruker APEX II with
electron spray ionization. The purity of the final compounds
was determined by HPLC on a Hewlett-Packard HP 1090 series
II liquid chromatograph using a Betasil C8 column (150 mm ꢀ
4.6 mm i.d., dp = 5 μm, Thermo Fisher Scientific, Waltham,
MA) at 230 and 254 nm, employing a gradient of 0.01 M
KH2PO4 (pH 2.3) and methanol as the solvent system with a
flow rate of 1.5 mL/min. All final compounds have a purity
of >96% (see Supporting Information for details).
4-(4-Fluorophenyl)-5-{2-[(1R,4R)-4-hydroxycyclohexylamino]-
pyridin-4-yl}-1,3-dihydroimidazol-2-one (5a). Compound 3b (0.18 g,
0.50 mmol) and trans-4-aminocyclohexanol (0.46 g, 4.0 mmol) were
combined in a reaction vessel. The reaction vessel was heated in a
microwave reactor for 4 h at 135 °C (initial power 250 W), after
which a stream of compressed air cooled the reaction vessel to room
temperature. The reaction mixture was purified by flash chroma-
tography (SiO2, DCM/EtOH, 8:1 to 1:1) to yield 62 mg (34%) of 5a
as a colorless solid. C20H21FN4O2 (Mr = 368.40); 1H NMR
(DMSO-d6) δ 1.14-1.21 (m, 4H, cyclohexyl), 1.73-1.89 (m, 4H,
cyclohexyl), 3.40-3.55 (m, 3H, 2ꢀCH cyclohexyl, OH), 6.19-6.29
(m, 3H, C3/C5-H Pyr, NH), 7.06-7.15 (m, 2H, C3/C5-H 4-F-Phe),
7.35-7.43 (m, 2H, C2/C6-H 4-F-Phe), 7.80 (d, J=5.4Hz, 1H, C6-H
Pyr), 10.52 (bs, 1H, NH), 10.59 (bs, 1H, NH); ESI-HRMS calcd,
C20H22FN4O2 [M þ H]þ 369.1721, obsd 369.1724.
(R)-4-(4-Fluorophenyl)-5-[2-(1-phenylethylamino)pyridin-4-yl]-
1,3-dihydroimidazol-2-one (5e). Compound 3a (0.20 g, 0.6 mmol)
and (R)-1-phenylethylamine (0.58 g, 6.0 mmol) were stirred in a
sealed glass tube for 10 h at 160 °C. After the mixture was cooled
to room temperature, the solvent was removed and the residue was
purified by flash chromatography (SiO2, DCM/EtOH, 95:5 to 8:2)
to afford 82 mg (37%) as a yellow solid. C22H19FN4O (Mr =
1
374.41); [R]2D0 þ36.4° (c 0.70, methanol); H NMR (DMSO-d6)
δ1.35(d, J=6.8 Hz, 3H, CH3), 4.79-4.89 (m, 1H, CH), 6.29-6.32
(m, 2H, C3/C5-H Pyr), 6.94 (d, J=7.2 Hz, 1H, NH), 7.16-7.26 (m,
7H, C6H5, C3/C5-H 4-F-Phe), 7.32-7.48 (m, 2H, C2/C6-H 4-F-
Phe), 7.78 (d, J=5.0 Hz, 1H, C6-H Pyr), 10.52 (bs, 1H, NH), 10.60
(bs, 1H, NH); ESI-HRMS calcd, C22H20FN4O[M þ H]þ 375.1616,
obsd 375.1619.
5-(4-Fluorophenyl)-4-(pyridin-4-yl)oxazol-2-amine (6). 2-Bromo-
2-(4-fluorophenyl)-1-(pyridin-4-yl)ethanone hydrobromide (150 mg,
0.40 mmol), urea (24 mg, 0.40 mmol), and DMF (1 mL) were
combined in a reaction vessel. The reaction vessel was heated in a
CEM microwave reactor for 10 min at 160 °C (initial power 250 W),
after which a stream of compressed air cooled the reaction vessel to
room temperature. Water and ethyl acetate were added, and the
organic layer was separated. This layer was washed with water
(3ꢀ), dried over Na2SO4, and concentrated in vacuo. The yellow

4802 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 12
Koch and Laufer
Scheme 9. Synthesis of 4-(4-Fluorophenyl)-5-(pyridin-4-yl)-1,3-dihydroimidazol-2-one (5f)a
a Reagents and conditions: (i) NaNO2, acetic acid, 10 °C to room temp; (ii) Pd/C 10%, iPrOH/HCl, H2, atmospheric pressure, room temp; (iii)
KOCN, DMF, reflux temperature.
Table 3. Evaluation of the Prepared Compounds 5a,d,e,f for p38R
MAP Kinase Inhibitory and LPS-Stimulated TNF-R Release from
HWB
(60 mL). The mixture was extracted three times with ethyl acetate
(80 mL). The combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The resulting yellow liquid (containing a
small amount of DMF) was treated with diethyl ether, and a yellow
solid was precipitated. The precipitate was filtered and purified by
flash chromatography (SiO2, EtOAc/MeOH, 1:0 to 1:1) to yield 48
mg (19%) as a yellow solid. C14H10FN3O (Mr=255.25); 1H NMR
(DMSO-d6) δ 7.18-7.30 (m, 4H, C3/C5-H 4-F-Phe, C3/C5-H Pyr),
7.40-7.47 (m, 2H, C2/C6-H 4-F-Phe), 8.41 (d, J=4.8 Hz, 2H, C2/
C6-H Pyr), 10.80 (bs, 2H, 2ꢀNH); ESI-HRMS, C14H11FN3O [M
þ H]þ 256.0881, obsd 256.0878.
IC50, μM
compd
5a
5d
p38Ra
TNF-Rb
0.023 ( 5.9e-4
0.049 ( 0.001
0.324 ( 0.017
0.468 ( 0.101
0.044 ( 0.004
2.92 ( 0.40
0.381 ( 0.05
ndc
ndc
5e
5f
SB203580
1.76 ( 0.43
a Mean ( SEM of three experiments. b Mean ( SEM of two experi-
Acknowledgment. The authors thank M. Goettert for bio-
logical testing and V. Schattel for molecular modeling.
ments. c Not determined.
Supporting Information Available: Experimental procedures
and analytical data for 3a,b, 5a,c-f, and 6-8. Descriptions of
the HWB assay and the molecular modeling. This material is
available free of charge via the Internet at http://pubs.acs.org.
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(9) Koch, P.; Schollmeyer, D.; Laufer, S. 5-(4-Fluorophenyl)-
4-(pyridin-4-yl)oxazol-2-amine. Acta Crystallogr., Sect. E: Struct.
Rep. Online 2010, E66, o917.
(10) Laufer, S.; Thuma, S.; Peifer, C.; Greim, C.; Herweh, Y.; Albrecht,
A.; Dehner, F. An immunosorbent, nonradioactive p38 MAP
kinase assay comparable to standard radioactive liquid-phase
assays. Anal. Biochem. 2005, 344, 135–137.
Figure 2. After geometric optimization, inhibitor 5d was docked in
the p38R active center. Possible hydrogen bonding interactions are
shown as dashed lines.
residue was suspended twice with DCM/EtOH, 95:5, filtered, and
finally dried. Yield 83 mg (81%); C14H10FN3O (Mr=255.25); 1H
NMR (DMSO-d6) δ 7.04 (s, 2H, NH2, exchangeable), 7.24-7.33
(m, 2H, C3/C5-H 4-F-Phe), 7.46-7.55 (m, 4H, C3/C5-H Pyr, C2/
C6-H 4-F-Phe), 8.51-8.54 (m, 2H, C2/C6-H Pyr); ESI-HRMS
calcd, C14H11FN3O[Mþ H]þ 256.0881, obsd 256.0879. The crystal
structure of 6 has been proven by X-ray analysis: Enraf-Nonius
CAD-4, Cu KR, SIR92, SHELXL97. Further details of the crystal
structure analysis are available in ref 9.
4-(4-Fluorophenyl)-5-(pyridin-4-yl)-1,3-dihydroimidazol-2-one (5f).
Compound 8 (0.26, 1.0 mmol) was dissolved in absolute DMF
(15 mL), and potassium cyanate (0.30 g, 2.0 mmol) was added. The
reaction mixture was heated to reflux temperature for 2.5 h. The
suspension was cooled to room temperature and diluted with water
(11) Abu Thaher, B.; Koch, P.; Schattel, V.; Laufer, S. Role of the
hydrogen bonding heteroatom-Lys53 interaction between the
p38alpha mitogen-activated protein (MAP) kinase and pyridinyl-
substituted 5-membered heterocyclic ring inhibitors. J. Med. Chem.
2009, 52, 2613–2617.