Design and synthesis of novel hydantoin-containing melanin-concentrating hormone receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2007.04.012

We report here new chemical series acting as antagonists of melanin-concentrating hormone receptor 1 (MCHR-1). Synthesis and structure-activity relationships are described leading to the identification of compounds with optimized in vitro pharmacological and in vitro ADME profiles. In vivo activity has been demonstrated in animal models of food intake and depression.

Full text of DOI:10.1016/j.bmcl.2007.04.012

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3754–3759
Design and synthesis of novel hydantoin-containing
melanin-concentrating hormone receptor antagonists
a
a
b
a
Fabrice Balavoine,a, ,ꢀ Patrice Malabre, Thierry Alleaume, Astrid Rey, Valerie Cherfils,
*
´
b
b
a
´ ´
Olivier Jeanneton, Sophie Seigneurin-Venin and Frederic Revah
aCerep, 19 avenue du Que´bec Courtaboeuf 1, 91951 Villebon sur Yvette, France
b
ˆ
Cerep, Le Bois l’Eveque, 86600 Celle L’Evescault, France
Received 26 February 2007; revised 31 March 2007; accepted 5 April 2007
Available online 10 April 2007
Abstract—We report here new chemical series acting as antagonists of melanin-concentrating hormone receptor 1 (MCHR-1). Syn-
thesis and structure–activity relationships are described leading to the identification of compounds with optimized in vitro pharma-
cological and in vitro ADME profiles. In vivo activity has been demonstrated in animal models of food intake and depression.
Ó 2007 Elsevier Ltd. All rights reserved.
Melanin-concentrating hormone (MCH) is a cyclic, 19-
amino acid peptide, highly conserved in sequence among
vertebrates. It is synthesized in cell bodies in the lateral
hypothalamus and zona incerta of the central nervous
system (CNS).1 Considerable evidence suggests the
involvement of MCH and one of its G-protein-coupled
receptors (MCHR-1) in a variety of physiological pro-
cesses such as the regulation of food intake and energy
metabolism, stress and anxiety syndromes.2 Intracere-
broventricular (icv) administration and chronic infu-
sions of MCH in rodents stimulate feeding behaviour
and result in hyperphagia and obesity.3,4 Transgenic
mice overexpressing MCH show obesity and resistance
to insulin.5 In contrast, targeted disruption of the
MCH gene in mice (mchÀ/À) results in a lean phenotype
due to hypophagia and increased metabolic rate,6 and
MCHR-1 deficient mice (mch1rÀ/À) are lean with de-
creased fat mass.7 In addition, central administration
of MCH in rats induces anxiety,8 and injection of
MCH into the nucleus accumbens shell of rats increases
their immobility in a forced swimming test (FST), sug-
gesting enhanced depressive behaviour.9 Therefore,
pharmacological blockade at MCHR-1 appears as a
promising approach for the treatment of obesity and
several mood disorders.
Since the molecular characterization of MCHR-1 in
1999,10 an important structural diversity of small molec-
ular weight drug-like MCHR-1 antagonists has been
produced.11 Several MCHR-1 antagonists have been
reported to induce hypophagia and weight loss in
rodents after single or multiple ip and/or po administra-
tions.12 In addition, some MCHR-1 antagonists have
been reported to produce effects similar to clinically used
antidepressants and anxiolytics in different animal mod-
els of depression and anxiety.13 Some MCHR-1 antago-
nists also demonstrated efficacy in rat models of urinary
incontinence.14 We report here novel hydantoin-con-
taining chemical series, acting as MCHR-1 antagonists
and significantly active in both rodent models of food
intake and depression.
Many of the previously reported MCHR-1 antagonists,
like those highlighted in Figure 1 (1,15 2,16 317 and 418),
show closely related chemical structures suggesting a
pharmacophore model where a hydrophobic moiety is
linked to a basic amine through a hydrogen-bond accep-
tor linker (amide or urea) and a nonspecific spacer.
Using the rhodopsin structure as a template of the trans-
membrane helical region of MCHR-1, the carbonyl
present in the linker was proposed to be involved in a
key interaction inside the MCHR-1 binding site, by
forming a hydrogen bond with the side chain of
Gln325 located on helix 6.17 A presumed interaction
Keywords: Hydantoin; Melanin-concentrating hormone; MCHR-1
antagonists; Obesity; Feeding; Depression.
*
Corresponding author. Tel.: +33 1 60 137 682; fax: +33 1 60 125
910; e-mail: fabrice.balavoine@quantum-genomics.com
´
Present address: Quantum Genomics Corp., Odyssee 2-12 chemin
des femmes, 91300 Massy, France.
ꢀ
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.04.012

F. Balavoine et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3754–3759
3755
Figure 1. Examples of MCHR-1 antagonists.
between the basic amine and Asp123 located in the third
transmembrane domain of MCHR-1 was also
reported.19
In order to identify new chemical series acting as
MCHR-1 antagonists, different hydrogen-bond acceptor
linkers were explored. According to the pharmacophore
model mentioned above, the chemical structures of
MCHR-1 antagonists drawn in Figure 1 were divided
in three regions: the western hydrophobic region A,
the central hydrogen bond acceptor region B and the
eastern region C, gathering the nonspecific spacer and
the basic amine. In a combinatorial approach, we de-
signed several ‘Am–Bn–Cp’ molecules by coupling two
hydrophobic western parts (biphenyl A1 and 4-phenoxy-
phenyl A2) to different hydrogen-bond acceptor linkers
and the eastern part C1 of compound 2 (Fig. 2).
Scheme 1. Reagents and conditions: (a) 1-Pyrrolidinyl-CH2CH2ClÆ
HCl, K2CO3, H2O, DMF, 80 °C (81%); (b) H2, 10% Pd/C, EtOH, rt,
1 atm(95%); (c)AmCOCl, CH2Cl2, NEt3, rtorAmCO2H, TBTU, HOBT,
DMF, rt (82–95%); (d) Am–NH2, CDI, THF, rt (75–87%); (e) Am–NH2,
ThioCDI, THF, rt (77–85%).
The methods followed to prepare the different ‘A1–Bn–C1’
and ‘A2–Bn–C1’ molecules where Bn is either an amide
(B1), urea (B2), thiourea (B3), 1-amino-thiazole (B4) or
hydantoin ring (B5 and B6) linker are outlined below
(Schemes 1–4). The target compounds 8a, 8b, 9a, 9b,
10a and 10b were prepared by the route described in
Scheme 1: 1-chloro-2-N-pyrrolidinyl-ethane reacted with
4-nitro-2-methoxyguiacol to form ether 6. Reduction of
this material by catalytic hydrogenation over palladium/
carbon in ethanol at room temperature and atmospheric
pressure afforded aniline 7. This key intermediate was
used to form amides 8a and 8b by reaction with the cor-
responding acyl chlorides in dichloromethane in the
presence of triethylamine, or by reaction with the corre-
sponding carboxylic acids using TBTU in DMF. Aniline
Figure 2. Combinatorial approach to identify new MCHR-1 antagonists.

3756
F. Balavoine et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3754–3759
were prepared by nucleophilic displacement of ethyl
2-bromo-acetate 13 in the presence of potassium
carbonate in acetonitrile. These intermediates were fur-
ther converted into ureas 15a and 15b by reaction with
aniline 7 in the presence of carbonyldiimidazole in THF.
Cyclization was then conducted in the presence of sodium
ethoxide in ethanol to yield compounds 16a and 16b.
Compounds 20a and 20b were prepared in three steps
from aniline 7 and the two methyl-ketones Am–COCH3
18a and 18b (Scheme 4). First, thiourea 17 was prepared
from aniline 7 and thiocarbonylimidazole by condensing
ammonia. Bromination of methyl-ketones 18a and 18b
was performed with bromine in diethyl ether to give a-
bromo-methyl-ketones 19a and 19b. These intermediates
reacted with thiourea 17 to afford the expected com-
pounds 20a and 20b, respectively.
Scheme 2. Reagents and conditions: (a) Ethyl-glyoxolate (50% in
toluene), Na2SO4,, 1,2 dichloroethane, 60 °C, 16 h, then H2, 10% Pd/C,
EtOH, rt, 1 atm (70%); Am–NCO, CH2Cl2, TEA (39–52%).
The different ‘Am–Bn–C1’ molecules were then evaluated
for binding to the MCHR-1 and compared to com-
pound 1 (Table 1). Amide analogues 8a and 8b appeared
to be the most potent compounds (Ki < 100 nM) when
compared with compound 1 (38 nM). Interestingly,
compound 12b showed, for MCHR-1, a moderate affin-
ity (Ki = 164 nM), but a good selectivity (Ki for MCHR-
2 > 10 lM). In addition, antagonism behaviour of 12b
was demonstrated in a MCH mediated calcium release
assay in recombinant CHO cells stably expressing
human MCHR-1. The specificity profile of 12b was
assessed by analyzing the binding of the compound to
a panel of 75 receptors, ion channels and transporters.20
Profile analysis demonstrated that 12b displayed a
significant affinity for the 5-HT2a receptor
(Ki = 330 nM), the 5-HT2c receptor (Ki = 880 nM) and
the muscarinic M4 receptor (Ki = 370 nM).
Scheme 3. Reagents and conditions: (a) Am–NH2, K2CO3, CH3CN,
80 °C (67–79%); (b) 7, CDI, THF, rt (75–87%); (c) EtONa, EtOH
(57–74%).
We hypothesized that the eastern region C1 of com-
pound 12b (A2–B5–C1 molecule) was primarily responsi-
ble for its high affinity for serotonin receptors. New
hydantoin analogues (A2–B5–Cp molecules) were de-
signed and screened in silico onto predictive binding
Table 1. Affinities of ‘Am–Bn–C1’ molecules for MCH-R1a
Scheme 4. Reagents and conditions: (a) ThioCDI, NH3 gas, CH2Cl2,
rt (85%); (b) Br2, Et2O (83–90%); (c) EtOH, reflux (65–82%).
Compound
Am
Bn
MCH-R1 Kib (nM)
7 was also converted into urea 9a and 9b and thiourea
10a and 10b by reaction with the corresponding aniline
Am–NH2 directly using carbonyldiimidazole or thiocar-
bonyl-diimidazole in THF.
1
8a
—
A1
A2
A1
A2
A2
A1
A2
A1
A2
A2
—
B1
B1
B2
B2
B3
B5
B5
B6
B6
B4
38
25
8b
9a
82
260
9b
101
Hydantoin analogues 13a and 13b were prepared in
three steps from aniline 7 (Scheme 2). The latter reacted
with ethyl 2-bromo-acetate to form a-amino-ester inter-
mediate 11. This material was added to the correspond-
ing isocyanates Am–NCO to give compounds 12a and
12b.
10b
12a
12b
16a
16b
20b
1090
415
164
>5000
365
1000
a All compounds were >95% pure by HPLC and characterized by 1H
NMR and LCMS. All values are mean values SEM (n P 2).
b Displacement of [125I][Phe13, Tyr19]-MCH from human recombinant
MCHR-1 expressed in CHO cells (Kd = 1 nm).
Similarly, hydantoin analogues 16a and 16b were pre-
pared in three steps starting from the corresponding ani-
lines Am–NH2 (Scheme 3). a-Amino-esters 14a and 14b

F. Balavoine et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3754–3759
3757
models towards 5-HT2a and 5-HT2c receptors. Benzyl-
idene derivative 21 was identified as a promising virtual
hit built on a more constrained scaffold.
benzylidene intermediate 25. Interestingly, only the for-
mation of the Z-isomer was observed as evidenced by
NMR. The H NMR chemical shifts of the N-methyl
1
analogue of 25, formed by stirring the latter with methyl
iodide under alkaline conditions, were compared to its
E-diastereoisomer prepared directly from 1-(4-phen-
oxy-phenyl)-3-methyl-hydantoin under similar Knoeve-
nagel conditions.21 Hydrolysis of the diethylacetal
group of 25 gave the corresponding aldehyde which
could be converted into compound 21 by reacting with
pyrrolidine in the presence of a reductive agent such as
triacetoxyborohydride.
Figure 3 reports overlays of two conformations of com-
pound 12b and compound 21 suggesting that the basic
amine (pyrrodinyl group) should fit into the same region
inside MCHR-1 binding site.
Compound 21 was prepared in five steps from ethyl isoc-
yanatoacetate 22 (Scheme 5). The latter reacted with
4-phenoxy-aniline to form urea 23 which can be further
transformed into hydantoin 24 under alkaline condi-
tions. 4-Diethoxyethylbenzaldehyde could react with
compound 24 under Knoevenagel conditions to give
Compound 21 was evaluated for binding to MCHR-1,
MCHR-2 and to the same panel of 75 pharmacological
targets. Compound 21 showed a high selectivity for
MCHR-1 versus MCHR-2 (Ki for MCHR-1 = 220 nm;
Ki for MCHR-2 > 10 lM) (Table 2). Only low affinity
was observed for serotonin receptors 5-HT2a
(Ki > 5 lM) and 5-HT2c (Ki > 10 lM). In fact, no signif-
icant activity (Ki < 500 nm) was found except for Ca2+
channel, L-verapamil site (330 nm). Antagonism behav-
iour of 21 was also demonstrated in a MCH mediated
calcium release assay. In addition, compound 21 showed
a drug-like in vitro ADME profile, particularly a good
Caco-2 permeability (>60 nm/s) predicting a significant
absorption after oral administration.
Based on the improvements of the selectivity against off-
target receptors, a series of benzylidine derivatives was
prepared to potentially elicit improved affinity for
MCHR-1. Starting from compound 25, reductive ami-
nation reactions were performed using 11 different
amines (Scheme 5). Compound 26k obtained from
(+/À)-3-hydroxypyrrolidine showed the best affinity
(Ki = 176 nm) (Table 2).
In order to establish the therapeutic potential of these
series of MCHR-1 antagonists, the effects of compounds
Figure 3. Conformation overlays of compound 12b and compound 21.
Table 2. Structure–activity relationship found on the series of benzyl-
idene derivatives built around compound 21a
Compound NHR1R2
MCH-R1 Kib (nM)
21
Pyrrolidine
220
>5000
>5000
341
26a
26b
26c
26d
26e
26f
26g
26h
26i
Cyclopentylamine
Benzylamine
Dimethylamine
Piperidine
Hexahydroazepine
Morpholine
>5000
357
>5000
707
2060
2-Dimethylaminoethylamine
4-Acetyl-piperazine
4-Phenyl-piperazine
4-Benzyl-piperazine
(+/À) 3-Hydroxypyrrolidine
>5000
>5000
176
Scheme 5. Reagents and conditions: (a) 4-phenoxy-aniline, CH2Cl2, rt
(94%); (b) NaOH, EtOH, rt overnight, then HCl concd, H2O, reflux
(93%); (c) 4-diethoxymethylbenzaldehyde, EtOH, MgSO4, pyrrolidine
(46%); (d) HCl (1 N), 2 h, 50 °C (92%); (e) NHR1R2, Na2SO4,
BH(OAc)3, CH2Cl2, rt, overnight (3–68%).
26j
26k
a See Table 1, footnote a.
b See Table 1, footnote b.

3758
F. Balavoine et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3754–3759
12b, 21 and 26k on food intake were assessed in over-
night fasted mice and compared to the anti-obesity drug,
sibutramine (MeridiaÒ) (Fig. 4). All compounds tested
induced a significant reduction of food intake after acute
ip administrations at 30 mg/kg. Cumulative food intake
was, respectively, reduced by 51%, 41% and 47% relative
to vehicle controls, 3 h after injection of compounds
12b, 21 and 26k. In addition, antidepressant potential
of compound 21 was assessed in a forced swimming test
in mice. When compared to control animals treated by
vehicle, immobility duration measured 30 min after
administration of compound 21 (30 mg/kg, ip) was sig-
nificantly reduced. Indeed, in vivo effects of compound
21 (À57%) were comparable to the effect of a clinically
used antidepressant, imipramine (10 mg/kg ip; À58%).
efforts still remain to be done to improve the hERG
selectivity of this novel chemical series.
Acknowledgments
The authors wish to acknowledge the technical contri-
bution to this work by Kevin Kennedy, Daniel Provost
and Aude Mangeol. The authors thank Eric Nicola¨ı,
´ ´
Eric Sartori and Frederique Barbosa for helpful
discussions.
References and notes
1. Bittencourt, J. C.; Presse, F.; Arias, C.; Peto, C.; Vaughan,
J.; Nahon, J. L.; Vale, W.; Sawchenko, P. E. J. Comp.
Neurol. 1992, 319, 218.
2. (a) Hervieu, G. Expert Opin. Ther. Targets 2003, 7, 495;
(b) Hervieu, G. Expert Opin. Ther. Targets 2006, 10, 211.
3. Rossi, M.; Choi, S. J.; O’Shea, D.; Miyoshi, T.; Ghatei, M.
A.; Bloom, S. R. Endocrinology 1997, 138, 351.
4. (a) Ito, M.; Gomori, A.; Ishihara, A.; Oda, Z.; Mashiko, S.;
Matsushita, H.; Yumoto, M.; Ito, M.; Sano, H.; Tokita, S.;
Moriya, M.; Iwaasa, H.; Kanatani, A. Am. J. Physiol.
Endocrinol. Metab. 2003, 284, E940; (b) Della-Zuana, O.;
Presse, F.; Ortola, C.; Duhault, J.; Nahon, J. L.; Levens, N.
Int. J. Obes. Relat. Metab. Disord. 2002, 26, 1289.
5. Ludwig, D. S.; Tritos, N. A.; Mastaitis, J. W.; Kulkarni,
R.; Kokkotou, E.; Elmquist, J.; Lowell, B.; Flier, J. S.;
Maratos-Flier, E. J. Clin. Invest. 2001, 107, 379.
Finally, acute toxicity of compound 21 and its effects on
general activity and behaviour were assessed based on a
modified Irwin’s method in mice.22 Compound 21
was given intraperitoneally to mice at 10, 30 and
100 mg/kg and comparisons were made with a vehicle
control group. No major side effect could be observed
while slight and transient prostration was noted within
the first 5 min after injection of the highest doses. How-
ever, potential risk of cardiac side-effects associated with
compound 21 was highlighted in a standard in vitro elec-
trophysiology assay on hERG K+ channel. When tested
at 1 lM, compound 21 induced a 73% current amplitude
inhibition.
In summary, we were able to design and to synthesize a
novel series of hydantoin-containing compounds, and
evaluate their potency as antagonists of MCHR-1.
SAR analysis showed that some compounds exhibited
activities below 200 nm. A rational chemical optimiza-
tion work was conducted to reduce off-target affinities
in order to minimize unexpected side-effects. This work
allowed the identification of compound 21, a lead mole-
cule significantly active in both rodent models of food
intake and depression. Further medicinal chemistry
6. Shimada, M.; Tritos, N. A.; Lowell, B.; Flier, J. S.;
Maratos-Flier, E. Nature 1998, 396, 670.
7. (a) Marsh, D. J.; Weingarth, D. T.; Novi, D. E.; Chen, H.
Y.; Trumbauer, M. E.; Chen, A. S.; Guan, X. M.; Jiang,
M. M.; Feng, Y.; Camacho, R. E.; Shen, Z.; Frazier, E.
G.; Yu, H.; Metzger, J. M.; Kuca, S. J.; Shearman, L. P.;
Gopal-Truter, S.; MacNeil, D. J.; Strack, A. M.; MacIn-
tyre, D. E.; Van der Ploeg, L. H.; Qian, S. Proc. Natl.
Acad. Sci. U.S.A. 2002, 99, 3240; (b) Chen, Y.; Hu, C.;
Hsu, C. K.; Zhang, Q.; Bi, C.; Asnicar, M.; Hsiung, H.
M.; Fox, N.; Slieker, L. J.; Yang, D. D.; Heiman, M. L.;
Shi, Y. Endocrinology 2002, 143, 2469.
8. Gonzalez, M. I.; Vaziri, S.; Wilson, C. A. Peptides 1996,
17, 171.
9. Georgescu, D.; Sears, R. M.; Hommel, J. D.; Barrot, M.;
Bolanos, C. A.; Marsh, D. J.; Bednarek, M. A.; Bibb, J.
A.; Maratos-Flier, E.; Nestler, E. J.; DiLeone, R. J.
J. Neurosci. 2005, 25, 2933.
2.5
2.0
*
1.5
1.0
0.5
0.0
*
*
10. (a) Chambers, J.; Ames, R. S.; Bergsma, D.; Muir, A.;
Fitzgerald, L. R.; Hervieu, G.; Dytko, G. M.; Foley, J. J.;
Martin, J.; Liu, W. S.; Park, J.; Ellis, C.; Ganguly, S.;
Konchar, S.; Cluderay, J.; Leslie, R.; Wilson, S.; Sarau, H.
M. Nature 1999, 400, 261; (b) Saito, Y.; Nothacker, H. P.;
Wang, Z.; Lin, S. H.; Leslie, F.; Civelli, O. Nature 1999,
400, 265; (c) Shimomura, Y.; Mori, M.; Sugo, T.;
Ishibashi, Y.; Abe, M.; Kurokawa, T.; Onda, H.; Nishim-
ura, O.; Sumino, Y.; Fujino, M. Biochem. Biophys. Res.
Commun. 1999, 261, 622.
11. McBriar, M. D. Curr. Opin. Drug Disc. Dev. 2006, 9, 496.
12. (a) Browning, A. Expert Opin. Ther. Patents 2004, 14, 313;
(b) Dyke, H. J.; Ray, N. C. Expert Opin. Ther. Patents
2005, 15, 1303; (c) Souers, A. J.; Gao, J.; Brune, M.; Bush,
E.; Wodka, D.; Vasudevan, A.; Judd, A. S.; Mulhern, M.;
Brodjian, S.; Dayton, B.; Shapiro, R.; Hernandez, L. E.;
Marsh, K. C.; Sham, H. L.; Collins, C. A.; Kym, P. R.
J. Med. Chem. 2005, 48, 1318.
*
* *
*
*
*
*
*
1h
2h
3h
5h
Time after food distribution
Vehicle
Sibutramine 10 mg/kg. i.p.
Compound 12b 30 mg/kg. i.p.
Compound 26k 30 mg/kg. i.p.
Compound 21 30 mg/kg. i.p.
Figure 4. Effects of Sibutramine (10 mg/kg, ip), compound 12b (30 mg/
kg, ip), compound 21 (30 mg/kg, ip) and compound 26k (30 mg/kg, ip)
on cumulative food intake in overnight fasted mice. Results are
expressed as means + SEM (n = 8 male OF1 mice per group).
*Indicates significant difference versus vehicle group-treated for
P < 0.05 (Dunett’s method).

F. Balavoine et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3754–3759
3759
13. (a) Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marza-
badi, M. R.; DeLeon, J.; Lagu, B.; Heurich, R.; Lichtblau,
H.; Shaposhnik, Z.; Daniewska, I.; Blackburn, T. P.;
Branchek, T. A.; Gerald, C.; Vaysse, P. J.; Forray, C. Nat.
Med. 2002, 8, 825; (b) Chaki, S.; Funakoshi, T.; Hirota-
Okuno, S.; Nishiguchi, M.; Shimazaki, T.; Iijima, M.;
Grottick, A. J.; Kanuma, K.; Omodera, K.; Sekiguchi, Y.;
Okuyama, S.; Tran, T. A.; Semple, G.; Thomsen, W.
J. Pharmacol. Exp. Ther. 2005, 313, 831; (c) Shimazaki, T.;
Yoshimizu, T.; Chaki, S. CNS Drugs 2006, 20, 801.
14. Salon, J. A.; Laz, T. M.; Nagormy, R.; Wilson, A. E.;
Craig, D. A. WO 04064774, 2004.
15. Takekawa, S.; Asami, A.; Ishihara, Y.; Terauchi, J.; Kato,
K.; Shimomura, Y.; Mori, M.; Murakoshi, H.; Kato, K.;
Suzuki, N.; Nishimura, O.; Fujino, M. Eur. J. Pharmacol.
2002, 438, 129.
16. Hertzog, D. L.; Al-Barazanji, K. A.; Bigham, E. C.;
Bishop, M. J.; Britt, C. S.; Carlton, D. L.; Cooper, J. P.;
Daniels, A. J.; Garrido, D. M.; Goetz, A. S.; Grizzle, M.
K.; Guo, Y. C.; Handlon, A. L.; Ignar, D. M.; Morgan, R.
O.; Peat, A. J.; Tavares, F. X.; Zhou, H. Bioorg. Med.
Chem. Lett. 2006, 16, 4723.
18. Souers, A. J.; Gao, J.; Wodka, D.; Judd, A. S.;
Mulhern, M. M.; Napier, J. J.; Brune, M. E.; Bush,
E. N.; Brodjian, S. J.; Dayton, B. D.; Shapiro, R.;
Hernandez, L. E.; Marsh, K. C.; Sham, H. L.;
Collins, C. A.; Kym, P. R. Bioorg. Med. Chem. Lett.
2005, 15, 2752.
19. Ulven, T.; Frimurer, T. M.; Receveur, J.-M.; Little, P. B.;
Rist, O.; Norregaard, P. K.; Ho¨gberg, T. J. Med. Chem.
2005, 48, 5684.
20. High-Throughput Profile performed according to Cerep’s
catalog (http://www.cerep.com).
21. Potin, D.; Launay, M.; Monatlik, F.; Malabre, P.;
Fabreguettes, M.; Fouquet, A.; Maillet, M.; Nicolai, E.;
Dorgeret, L.; Chevallier, F.; Besse, D.; Dufort, M.;
Caussade, F.; Ahmad, S. Z.; Stetsko, D. K.; Skala, S.;
Davis, P. M.; Balimane, P.; Patel, K.; Yang, Z.; Marathe,
P.; Postelneck, J.; Townsend, R. M.; Goldfarb, V.; Sheriff,
S.; Einspahr, H.; Kish, K.; Malley, M. F.; DiMarco, J. D.;
Gougoutas, J. Z.; Kadiyala, P.; Cheney, D. L.; Tejwani,
R. W.; Murphy, D. K.; Mcintyre, K. W.; Yang, X.; Chao,
S.; Leith, L.; Xiao, Z.; Mathur, A.; Chen, B. C.; Wu, D.
R.; Traeger, S. C.; McKinnon, M.; Barrish, J. C.; Robl, J.
A.; Iwanowicz, E. J.; Suchard, S. J.; Dhar, T. G. J. Med.
Chem. 2006, 49, 6946.
17. Clark, D. E.; Higgs, C.; Wren, S. P.; Dyke, H. J.; Wong,
M.; Norman, D.; Lockey, P. M.; Roach, A. G. J. Med.
Chem. 2004, 47, 3962.
22. Irwin, S. Psychopharmacologia 1968, 13, 222.