Design and synthesis of quinolin-2(1H)-one derivatives as potent CDK5 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.07.045

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine protein kinase and its deregulation is implicated in a number of neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Using active site homology modeling between CDK5 and CDK2, we explored several different chemical series of potent CDK5 inhibitors. In this report, we describe the design, synthesis, and CDK5 inhibitory activities of quinolin-2(1H)-one derivatives.

Full text of DOI:10.1016/j.bmcl.2007.07.045

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5384–5389
Design and synthesis of quinolin-2(1H)-one derivatives
as potent CDK5 inhibitors
Wenge Zhong,a,* Hu Liu,a, Matthew R. Kaller,a Charles Henley,b Ella Magal,b
Thomas Nguyen,a Timothy D. Osslund,a David Powers,a Robert M. Rzasa,a
Hui-Ling Wang,a Weiya Wang,b Xiaoling Xiong,a
Jiandong Zhanga and Mark H. Normana
aChemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
bDepartment of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Received 5 June 2007; revised 28 July 2007; accepted 30 July 2007
Available online 6 August 2007
Abstract—Cyclin-dependent kinase 5 (CDK5) is a serine/threonine protein kinase and its deregulation is implicated in a number of
neurodegenerative disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, and ischemic stroke. Using active site homol-
ogy modeling between CDK5 and CDK2, we explored several different chemical series of potent CDK5 inhibitors. In this report, we
describe the design, synthesis, and CDK5 inhibitory activities of quinolin-2(1H)-one derivatives.
Ó 2007 Elsevier Ltd. All rights reserved.
H
H
N1
H
N
Cyclin-dependent kinase 5 (CDK5) is a serine/threonine
protein kinase believed to play a critical role in the early
development of the central nervous system.1,2 It has no
known involvement in cell cycle progression, but it is
shown to be involved in cellular processes such as neuronal
differentiation,3 cell adhesion,4 and axonal guidance.5
Recently, a large body of evidence suggests that deregu-
lation of CDK5 is implicated in the pathology of a num-
8
5
N2
O
O
N
O
N
7
6
N1 N3
H
N
3
4
S
S
S
N
N
N
1
2
3
N
N
N
Figure 1. CDK5 inhibitors.
ber of neurodegenerative disorders.6–8 As
a
consequence, CDK5 inhibitors are of potential thera-
peutic uses for diseases such as Alzheimer’s disease,6
Parkinson’s disease,7 amyotrophic lateral sclerosis,8
and ischemic stroke.9 Several different classes of
CDK5 inhibitors have recently appeared in the
literature.10
IC50 = 4.6 nM; CDK5 IC50 = 15 nM), we developed an
active site homology model of CDK5 for further explo-
ration and optimization of potent CDK5 inhibitors.13
To mimic the intramolecular hydrogen bond between
N1 and N3–H in urea 1, which was believed to help
pre-organize the inhibitor to a U-shaped binding con-
formation, we investigated ring-constrained CDK5
inhibitors (Fig. 1). We recently described a series of
3,4-dihydro-1H-quinazolin-2-ones that showed potent
CDK5 inhibitory activities (2, CDK5 IC50 = 79 nM).13
To extend our investigations of ring-constrained sys-
tems, we examined the analogous quinolin-2(1H)-one
derivatives. We proposed that quinolin-2(1H)-one deriv-
atives such as 3 should overlay ideally with the core
structures of the 3,4-dihydro-1H-quinazolin-2-ones and
the same donor–acceptor hydrogen bond pattern for
binding would project to the linker residues of the
CDK5 active site. Herein we report the design, synthesis,
From high throughput screening efforts, we identified a
series of acyclic thiazolo-urea compounds as potent
CDK2 and CDK5 inhibitors.11,12 Based on the co-crys-
tal structure of CDK2 and acyclic urea 1 (Fig. 1, CDK2
Keywords: Kinase; Neurodegenerative disorders; CDK5 inhibitor;
Quinolin-2(1H)-one.
*
Corresponding author. Tel.: +1 805 447 5732; fax: +1 805 480
3016; e-mail: zwenge@amgen.com
Current address: Cambridge Laboratories, Pfizer Global R&D, 620
Memorial Drive, Cambridge, MA 02139, USA.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.07.045

W. Zhong et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5384–5389
5385
and CDK5 inhibitory activities of the quinolin-2(1H)-
one derivatives.
ing acid 10, which was coupled to o-substituted anilines
11 using EDCI–HOAt to afford key intermediates 12.
Treatment of 12 with strong bases such as KOtBu or
LiHMDS led to the formation of the 4-substituted quin-
olin-2(1H)-one derivatives 13a–g.17
A general synthesis of the quinolin-2(1H)-one deriva-
tives is outlined in Scheme 1. Treatment of commercially
available thioisonicotinamide 4 with chloroacetoacetate
in refluxing MeOH provided methyl 2-(2-(pyridin-4-
yl)thiazol-4-yl)acetate 5.14 Alkylation of 5 with appro-
priately substituted o-nitro benzylbromides 6 afforded
intermediates 7. Subsequent reductive cyclization of 7
with Fe/NH4Cl in refluxing aqueous EtOH furnished
To prepare a wide range of analogs that were intended
to replace the pyrid-4-yl group of 3, a flexible three-step
parallel synthesis strategy based on thiazole ring forma-
tion was developed (Scheme 3). Using this method, read-
ily available 2-aminobenzaldehydes 14 were reacted with
diketene to provide 3-acetyl-quinolin-2(1H)-ones 15 in
good yield.18 Treatment of 15 with 5,5-dibromobarbitu-
ric acid (0.55 equiv) in refluxing THF afforded the versa-
tile intermediate 3-bromoacetyl-quinolin-2(1H)-ones 16,
which precipitated out upon cooling of the reaction mix-
ture.19 In the final step, thiazole formation of 16 with a
variety of thioamides in MeOH furnished quinolin-
2(1H)-one derivatives 17a–p.14 In most cases the final
products precipitated from the reaction mixtures and
simple filtration was sufficient for obtaining final prod-
ucts with >95% purity. It should be noted that this
chemistry was also applied to the synthesis of inhibitors
9g–i, wherein two sequential steps of ester hydrolysis
and amide formation were followed.
3,4-dihydro-quinolin-2(1H)-ones
8 in good overall
yield.15 Treatment of 8 with NBS/AIBN in CCl4 at
85 °C proceeded smoothly to provide quinolin-2(1H)-
one derivatives 3, 9a and b, or 9d–f.16 For analogs 9c,
the synthesis was completed with ester hydrolysis using
lithium hydroxide in aqueous MeOH and amide forma-
tion using standard EDCI–HOAt coupling conditions.
An alternative method for synthesizing derivatives
bearing substituents at the 4-position of the quinolin-
2(1H)-one core was employed. As shown in Scheme 2,
compound 5 was hydrolyzed to provide the correspond-
NO2
R
The derivatives prepared in this study were evaluated for
their ability to inhibit purified human CDK5. Com-
pounds were screened in an HTRF human CDK5/p25
assay that was run in the presence of 25 lM ATP and
1 lM histone-H1. The IC50 values were determined from
dose–response curves and are reported in Tables 1–4 as
the average of two replications (unless otherwise
indicated).
O
Br
NO2
MeO
CO2Me
N
S
R
6
i
ii
H2N
S
S
N
N
4
5
7
N
N
H
H
N
N
O
N
O
N
R
R
iii
iv
S
S
To validate the quinolin-2(1H)-one as a viable alterna-
tive core to the 3,4-dihydro-1H-quinazolin-2-one, we
prepared compound 3 and found it to be a potent
CDK5 inhibitor (IC50 = 54 nM). With this encouraging
result, we started our investigation by systematically
introducing various modifications at the 5-, 6-, and 7-
positions of the quinolin-2(1H)-one core. Table 1 high-
lights the findings. At the 5-position, an ester group
was well tolerated (9a, IC50 = 33 nM), but a carboxyl
group was detrimental to activity (9b, IC50 > 10 lM).
3
& 9a-f
8
N
N
Scheme 1. Reagents and conditions: (i) ClCH2COCH2CO2CH3,
MeOH, reflux, 12 h; (ii) LiHMDS, THF, ꢀ78 °C, 1.5 h; (iii) Fe,
NH4Cl, H2O–EtOH (1:1), 80 °C, 2 h; (iv) NBS, AIBN, CCl4, 85 °C,
2 h; for 9c, additional steps were: (a) LiOH, MeOH, H2O, 75 °C, 2 h;
i
(b) EDCI, HOAt, Pr2NEt, amine, CH2Cl2, 0 °C—room temperature,
12 h.
O
O
HO
MeO
NH2
X
i
H
S
+
R
S
NH2
O
N
O
i
ii
N
N
R
R
O
5
10
11, X = CO2Me,
N
N
CH3
COPh,
COMe,
or CN.
14
15
H
H
N
N
O
H
N
H
N
O
N
O
O
N
iii
R
R
R
R
ii
iii
X
O
S
N
S
S
R1
Br
16
9g-i
17a-p
R'
13a-g
12, X = CO2Me,
COPh,
N
N
COMe,
Scheme 3. Reagents and conditions: (i) diketene, DMAP, CH2Cl2, 50–
80%; (ii) 5,5-dibromobarbituric acid (0.55 equiv), THF, reflux, 2–4 h,
70–80%; (iii) R0-CSNH2, MeOH, 75 °C, 12 h; for 9g–i, additional steps
were: (a) NaOH, MeOH, H2O, 75 °C, 2 h; (b) pivaloyl chloride,
iPr2NEt, amine, CH2Cl2, 0 °C—room temperature, 12 h.
or CN.
Scheme 2. Reagents and conditions: (i) LiOH, H2O, MeOH, 75 °C,
2 h; (ii) EDCI, HOAt, iPr2NEt, CH2Cl2, 0 °C—room temperature,
12 h; (iii) KOtBu or LiHMDS, THF, 0 °C—room temperature, 12 h.

5386
W. Zhong et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5384–5389
Table 1. SAR of substituted 3-(2-pyridin-4-yl-thiazol-4-yl)quinolin-
2(1H)-ones
Table 3. SAR of pyridin-4-yl replaced thiazol-4-yl-quinolin-2(1H)-
ones
H
H
N
O
N
R7
R6
N
O
N
S
R
S
R5
Compound
R
CDK5/p25 (IC50; nM)a
54 33
N
3
Compound
R5
H
R6
R7
CDK5/p25
(IC50; nM)a
N
3
H
H
H
H
54 33
33 25
17a
17b
17c
17d
17e
17f
17g
17h
17i
1400 81
410 190
50 26
9a
CO2Me
9b
H
H
>10,000
CO2H
S
N
O
9c
H
H
480 100
9d
9e
9f
H
H
H
F
H
H
110 69
11 7.0
6.3b
N
Cl
H
Cl
CF3
>10,000b
>10,000b
>10,000b
170 77 nM
24 15
8.3b
N
9g
H
H
N
Cl
Cl
O
N
N
N
9h
9i
H
H
H
H
4.4 0.7
2.7b
O
O
a At least two independent experiments were performed for each
compound to determine the IC50 values.
b One experiment was performed to determine the IC50 value.
NH2
OH
O
>10,000b
Table 2. SAR of substituted 3-(2-pyridin-4-yl-thiazol-4-yl)quinolin-
2(1H)-ones
a At least two independent experiments were performed for each
compound to determine the IC50 values.
b One experiment was performed to determine the IC50 value.
H
N
O
N
R6
S
R4
Tertiary amido groups were then incorporated at this
position. It had been established earlier that such amido
groups at the corresponding position in the acyclic urea
series were beneficial for activities (data not shown).
Surprisingly, we did not observe a similar SAR trend
in the quinolin-2(1H)-one series. The best of these amido
analogs, a diethylamido derivative 9c, was only moder-
ately active (IC50 = 480 nM). While the 6-fluoro analog
9d was slightly less active than compound 3, the 6-chloro
analog 9e was about 5-fold more potent (IC50 = 11 nM).
As in the 3,4-dihydro-1H-quinazolin-2-one series, the 7-
position was found to be the most permissive to modifi-
cations.13 For example, introduction of a CF3 group (9f)
increased the potency by approximately 9-fold. In con-
trast to the SAR trend observed at the 5-position, a vari-
ety of analogs containing tertiary amido groups at this
position were among the most potent CDK5 inhibitors
in this series with IC50 values ranging from 2.7 to
8.3 nM (9g–i). This was not very surprising since the
CDK5 active site homology model suggested that the
N
Compound
R4
R6
CDK5/p25 (IC50; nM)a
3
13a
H
OH
H
H
54 33
160 98
13b
H
470 220
13c
13d
13e
CH3
NH2
NH2
H
H
Cl
2800 1500
11 7.0
3.8b
N
13f
NH2
NH2
250 210
120 36
N
13g
N
a At least two independent experiments were performed for each
compound to determine the IC50 values.
b One experiment was performed to determine the IC50 value.

W. Zhong et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5384–5389
5387
Table 4. SAR of pyridin-4-yl replaced thiazol-4-yl-quinolin-2(1H)-one
arylsulfone derivatives
Facilitated by a three-step parallel synthetic strategy,
we were able to readily access the desired analogs.
H
N
O
N
Table 3 summarizes the CDK5 inhibitory activities of
selected compounds with alternatives to the pyrid-4-yl
group. Not surprisingly, replacement of the pyrid-4-yl
group with a phenyl group resulted in a significant de-
crease of activity (17a, IC50 = 1400 nM). This may be
attributed to the loss of the ability to interact with the
salt bridge formed between Lys33 and Asp144. Consis-
tent with this observation, the thien-3-yl analog 17b also
exhibited an 8-fold decrease in activity. However, the
pyrid-3-yl analog 17c was equipotent as compound 3,
despite the less than optimal positioning of the 3-N
atom for simultaneous interactions with both Lys33
and Asp144 in the homology model. We attempted to
improve potency of 17a by introducing substituents
onto the phenyl ring. Substitution scanning with chloro
at the 2-, 3-, or 4-position of the phenyl ring of 17a pro-
vided inhibitors with additional loss of activity (17d–f,
Table 3), suggesting unfavorable van der Waals interac-
tions between this portion of the inhibitor and the active
site of CDK5. However, a closer examination of the
homology model revealed that the Lys33–Asp144 salt
bridge was at the edge toward a solvent exposed area.
We reasoned that certain hydrophilic substituents at
the 4-position of the phenyl ring may be tolerated. In-
deed, we found that introduction of an amino or a hy-
droxyl group at the 4-position afforded potent
inhibitors 17g and 17h, with the latter being 2-fold more
potent than compound 3. The observed potency
increases may be attributed to the favorable interactions
of the amino or the hydroxy group with the
Lys33–Asp144 salt bridge. The hydrogen donor abilities
of these groups appeared to be important, as the 4-meth-
oxy derivative 17i was >400-fold less active than 17h.
S
R
Compound
R
CDK5/p25 (IC50; nM)a
54 33
3
N
O
O
O
S
S
17j
17k
17l
29 19
10 1.1
2.1 1.1
O
N
O
O
O
S
S
S
O
17m
17n
240 150
300 160
Cl
O
O
O
O
S
S
17o
6900 1000
120 47
O
S
( )-17p
a At least two independent experiments were performed for each
compound to determine the IC50 values.
7-position is close to a solvent exposed area from the ac-
tive site and should be more tolerant to substitutions.
In order to probe different potential binding interactions
at the CDK5 active site, we explored other structurally
diverse pyrid-4-yl alternatives. We discovered an inter-
esting series of quinolin-2(1H)-one arylsulfone deriva-
tives as potent CDK5 inhibitors (Table 4). For
example, arylsulfone derivatives 17j, 17k, and 17l exhib-
ited potencies of 29, 10, and 2.1 nM, respectively. The
aryl ring was found to be sensitive to modifications as
seen with the introduction of chloro at the 4-position
of the phenyl ring of 17j leading to >8-fold decrease in
activity (17m, IC50 = 240 nM). Attempts to replace the
aryl rings with simple alkyl groups were unsuccessful.
While the methylsulfone derivative 17n retained moder-
ate potency, the tert-butylsulfone analog 17o was >240-
fold less active. Finally, we determined that the sulfone
moiety was important for activity. As shown in Table 3,
the corresponding mono-sulfoxide analog of 17j dis-
played an IC50 of 1100 nM (( )-17p).
Table 2 summarizes the results from the 4-substituted
quinolin-2(1H)-one derivatives. In comparison to com-
pound 3, substitution with a hydroxyl, phenyl, or methyl
group at this position provided inhibitors 13a, 13b, and
13c that were 3-, 9-, and 55-fold less active, respectively.
However, an amino group at this position provided
superior CDK5 activity. Compound 13d was about 5-
fold more potent than compound 3. With the 4-amino
group in place, additional substituents were amended
at the 6-position. While small electron-withdrawing
group such as chloro resulted in an additional 3-fold in-
crease in potency over 13d, large electron-donating
groups such as 1-piperidinyl or 4-methyl-1-piperizinyl
groups resulted in a 10- to 20-fold decrease in activity
(13e–g).
In the 3,4-dihydro-1H-quinazolin-2-one series, we had
shown that the pyrid-4-yl group was optimal for enzyme
activity.13 In the homology model, it was believed that
the pyrid-4-yl group is engaged in a hydrogen bond net-
work involving a salt bridge formed by two highly con-
served residues Lys33 and Asp144. However,
considering the potential Cyp P450 inhibitory liabilities
frequently associated with pyridyl-containing com-
pounds,20 we investigated replacements for this group.
To better understand the binding mode of the quino-
lin-2(1H)-one arylsulfone inhibitors, we chose 17j as a
representative example and modeled it in the CDK5
active site.21 In the model illustrated in Figure 2, the
inhibitor binds in a J-shaped conformation whereby
the quinolin-2(1H)-one core forms two key hydrogen
bonds to Cys83 in the linker. Consistent with the

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W. Zhong et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5384–5389
References and notes
1. Dhavan, R.; Tsai, L.-H. Nat. Rev. Mol. Cell Biol. 2001, 2,
749.
2. Smith, D. S.; Tsai, L.-H. Trends Cell Biol. 2003, 12(1), 28.
3. Nikolic, M.; Dudek, H.; Kwon, Y. T.; Ramos, Y. F.; Tsai,
L. H. Genes Dev. 1996, 10, 816.
4. Kwon, Y. T.; Gupta, A.; Zhou, Y.; Mikolic, M.; Tsai, L.
H. Curr. Biol. 2000, 10, 363.
5. Kwon, Y. T.; Tsai, L. H.; Crandell, J. E. J. Comp. Neurol.
1999, 415, 218.
6. (a) Tsai, L.-H.; Lee, M.-S.; Cruz, J. Biochim. Biophys. Acta
2004, 1697, 137; (b) Maccioni, R. B.; Otth, C.; Concha, I.
I.; Munoz, J. P. Eur. J. Biochem. 2001, 268, 1518.
7. Smith, P. D.; Crocker, S. J.; Jackson-Lewis, V.; Jordan-
Sciutto, K. L.; Hayley, S.; Mount, M. P.; O’Hare, M. J.;
Callaaghan, S.; Slack, R. S.; Przedborski, S. Proc. Natl.
Acad. Sci 2003, 100, 13650.
8. Patzke, H.; Tsai, L.-H. Trends Neurosci. 2002, 25, 8.
9. (a) Wang, J.; Lui, S.; Fu, Y.; Wang, J. H.; Lu, Y. Nat.
Neurosci. 2003, 6, 1039; (b) Weishaupt, J. H.; Kussmaul,
L.; Grotsch, P.; Heckel, A.; Rohde, G.; Romig, H.; Bahr,
M.; Gillardson, F. Mol. Cell. Neurosci. 2003, 24, 489; (c)
Wang, F.; Corbett, D.; Osuga, H. J. Cereb. Blood Flow
Metab. 2002, 22, 171; (d) Osuga, H.; Osuga, S.; Wang, F.;
Fetni, R.; Hogan, M. J.; Slack, R. S.; Hakim, A. M.;
Ikeda, J. E.; Park, D. S. Proc. Natl. Acad. Sci 2000, 97,
10254.
10. (a) Gompel, M.; Leost, M.; Bal de Kier Joffe, E.; Puricelli,
L.; Franco, L. H.; Palermo, J.; Meijer, L. Bioorg. Med.
Chem. Lett. 2004, 14, 1703; (b) Polychronopoulos, P.;
Magiatis, P.; Skaltsounis, A.-L.; Myrianthopoulos, V.;
Mikros, E.; Tarricone, A.; Musacchio, A.; Roe, S. M.;
Pearl, L.; Maryse, L.; Greengard, P.; Meijer, L. J. Med.
Chem. 2004, 47, 935; (c) Zapata-Torres, G.; Opazo, F.;
Salgado, C.; Munoz, J. P.; Krautwurst, H.; Mascayano,
C.; Sepulveda-Boza, S.; Maccioni, R. B.; Cassels, B. K.
J. Nat. Prod. 2004, 67, 416; (d) Ortega, M. A.; Montoya,
M. E.; Zarranz, B.; Jaso, A.; Aldana, I.; Leclerc, S.;
Meijer, L.; Monge, A. Bioorg. Med. Chem. 2002, 10, 2177;
(e) Chang, Y. T.; Gray, N. S.; Rosania, G. R.; Sutherlin,
D. P.; Kwon, S.; Norman, T. C.; Sarohia, R.; Leost, M.;
Meijer, L.; Schultz, P. G. Chem. Biol. 1999, 6, 361; (f)
Helal, C. J.; Sanner, M. A.; Cooper, C. B.; Gant, T.;
Adam, M.; Luca, J. C.; Kang, Z.; Kupchinsky, S.;
Ahlijanian, M. K.; Tate, B.; Menniti, F. S.; Kelly, K.;
Peterson, M. Bioorg. Med. Chem. Lett. 2004, 14, 5521.
11. Santora, V.; Askew, B.; Ghose, A.; Hague, A.; Kim, T. S.;
Laber, E.; Li, A.; Lian, B.; Liu, G.; Norman, M. H.;
Smith, L.; Tasker, A.; Tegley, C.; Yang, K. International
Patent WO 02/014311, 2002.
Figure 2. Binding model of compound 17j in the active site of CDK5.
Proposed H-bonding network is shown in green. Carbon atoms of
compound 17j are shown in green, carbon atoms of active site residues
in brown, nitrogen atoms in blue, oxygen in red, and sulfur in yellow.
3,4-dihydro-1H-quinazolin-2-one series, and our origi-
nal hypothesis, the thiazole ring extends into the con-
served hydrophobic pocket lined in part by Phe80 and
forms an edge-to-face van der Waals interaction with
Phe80. The phenyl group of the arylsulfone moiety
provides additional hydrophobic interactions. Interest-
ingly, one of the oxygen atoms of the sulfone moiety
interacts with the Lys33–Asp144 salt bridge by form-
ing a hydrogen bond to the e-NH2 group of Lys33,
while the other oxygen atom forms a potential hydro-
gen bond with the backbone NH of Asp144. This
mode of interaction differs significantly from that of
the pyrid-4-yl group in the co-crystal structure of
CDK2 and inhibitor 1 and provides a rational basis
to explain the observed SAR trends of these quino-
lin-2(1H)-one arylsulfone inhibitors.
To summarize, using active site homology modeling
based on crystallographic data from the acyclic urea
1/CDK2 complex, we rationally designed and synthe-
sized a novel series of quinolin-2(1H)-one derivatives
as potent CDK5 inhibitors. From these studies, we
found that the 4-amino substituent at the quinolin-
2(1H)-one core was well tolerated and the 7-position
was the most permissive for modifications. In our ef-
fort to explore pyrid-4-yl alternatives, we discovered
a series of arylsulfone compounds as potent CDK5
inhibitors. A binding model was developed for an
exemplary compound from this class of compounds
to account for the major binding interactions. Further
investigations toward improving solubility and selec-
tivity of the quinolin-2(1H)-one derivatives will be re-
ported in due course.
12. Hever, G.; Wang, J.; Kuang, R.; Zhang, M.; Jiao, S.;
Louis, J. C.; Magal, E. CDK5 Inhibition as a Target for
Neuroprotection in Rat Model of Middle Cerebral Artery
Occlusion. Society for Neuroscience 33rd Annual Meet-
ing, New Orleans, 2003.
13. Rzasa, R. M.; Kaller, M.; Liu, G.; Magal, E.; Nguyen,
T.; Osslund, T. D.; Powers, D.; Santora, V. J.; Wang,
H.-L.; Xiaoling Xiong, X.; Zhong, W.; Norman, M. H.
Bioorg. Med. Chem. 2007. doi:10.1016/j.bmc.2007.
07.005.
14. El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. Tetrahedron Lett. 2002, 43, 3193.
´
15. Palacios, F.; Herran, E.; Rubials, G. J. Org. Chem. 1999,
64, 6239.
Acknowledgments
16. Teramoto, S.; Tanaka, M.; Shimizu, H.; Fujioka, T.;
Tabusa, F.; Imaizumi, T.; Yoshida, K.; Fujiki, H.; Mori,
T.; Sumida, T.; Tominaga, M. J. Med. Chem. 2003, 46,
3033.
We are grateful to Dr. Vellarkad Viswanadhan for mod-
eling support and Dr. Ning Xi for proofreading this
manuscript and providing valuable suggestions.

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5389
17. Rehwald, M.; Gewald, K.; Lankau, H.; Unverferth, K.
Heterocycles 1997, 45, 483.
18. Davis, S. E.; Rauckman, B. S.; Chan, J. H.; Roth, B.
J. Med. Chem. 1989, 32, 1936.
19. Burkhart, J. P.; Gates, C. A.; Laughlin, M. E.; Resvick, R.
J.; Peet, N. P. Bioorg. Med. Chem. 1996, 4, 1411.
20. Fontana, E.; Dansette, P. M.; Poli, S. M. Curr. Drug
Metab. 2005, 6, 413.
21. The arylsulfone analog 17k was generated using
Insight (2000) software with in-house X-ray structure
of a related compound as the starting point. Ab
initio calculations using Density Functional Theory
as implemented in Gaussian98 software, utilizing the
B3LYP hybrid density functional and the 6-31G*
basis set at B3LYP/6-31G* level, were carried out
on these molecules. These were aligned using Insight
II, Transform/Superimpose options. Solvation free
energies were calculated using the Polarizable Con-
tinuum Model (PCM) implemented in Gaussian 98
software.