5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones: Dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors. Part 3

Article abstract of DOI:10.1016/j.bmcl.2010.09.085

5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT₁ autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The

Full text of DOI:10.1016/j.bmcl.2010.09.085

Bioorganic & Medicinal Chemistry Letters 20 (2010) 7092–7096
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones
and 3,4-dihydro-2(1H)-quinolinones: Dual-acting 5-HT1 receptor antagonists
and serotonin reuptake inhibitors. Part 3
Steven M. Bromidge a, , Roberto Arban b, Barbara Bertani b, Manuela Borriello b, Anna-Maria Capelli b,
⇑
a
b
Romano Di-Fabio b, Stefania Faedo b, Massimo Gianotti b, , Laurie J. Gordon , Enrica Granci ,
⇑
Alessandra Pasquarello b, Simone K. Spada b, Angela Worby a, Laura Zonzini b, Valeria Zucchelli b
a Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
b Neurosciences CEDD, GlaxoSmithKline, Medicines Research Centre, Via A. Fleming 4, Verona 37135, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 May 2010
Revised 14 September 2010
Accepted 15 September 2010
Available online 27 September 2010
5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quin-
olinones have been identified with different combinations of 5-HT1 autoreceptor antagonist and hSerT
potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at tar-
gets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different
pharmacological profiles in a range of animal behavioral and disease models.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Depression
Serotonin
5-HT
5-HT1 autoreceptor antagonists
Serotonin transporter inhibitors
Over the past decades, a wealth of preclinical and clinical evi-
dence has confirmed a link between extracellular levels of seroto-
nin (5-HT) and a plethora of psychiatric indications, in particular
anxiety and depression.1 In fact, enhanced serotonergic neuro-
transmission has become the unifying mechanism of action of
modern day antidepressants and the selective serotonin reuptake
inhibitors (SSRIs) have become established as the most effective
antidepressant agents in current clinical use.2 Despite the success
of SSRIs, one undesirable characteristic is a long latency to thera-
peutic onset which is hypothesized to be due to the requirement
for desensitisation of 5-HT1 autoreceptors to maintain increased
5-HT levels.3 This is consistent with preclinical neurochemical
studies which have demonstrated that SSRIs such as paroxetine re-
quire chronic dosing (14–21 days) in order to enhance extracellu-
lar 5-HT levels in guinea pig dentate gyrus and rat frontal cortex
but have no effect after acute administration.4
5-HT levels.5 Blockade of 5-HT1A/B/D autoreceptors, with or without
concomitant SerT inhibition, rapidly increases brain 5-HT levels
and consequently should provide a fast onset of antidepressant/
anxiolytic action relative to current therapies.6
We have previously reported potent 5-HT1A/B/D receptor antag-
onists both with and without additional hSerT reuptake inhibitory
activity including 1 (SB-649915) (Fig. 1).7 More recently, we
disclosed
a
series of 6-[2-(4-aryl-1-piperazinyl)ethyl]-2H-1,4-
R
O
O
N
O
N
R
N
O
O
O
N
N
N
N
O
N
N
5-HT1 autoreceptors are located on both the cell bodies (5-HT1A
,
5-HT1B and 5-HT1D receptor subtypes) and nerve terminals (5-HT1B
and 5-HT1D receptor subtypes) of 5-HT neurons.5 They are widely
distributed in the brain and in addition to serotonin transporters
(SerT) are known to have a major role in the control of synaptic
N
N
N
1 (SB-649915)
2 R = H (SB-744185)
3 R = Me
4 R = H
5 R = Me
⇑
Corresponding authors. Tel.: +44 1235861561; fax: +44 1235863139.
E-mail address: steven.bromidge@evotec.com (S.M. Bromidge).
Figure 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.085

S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7092–7096
7093
benzoxazin-3(4H)-ones (such as 2,3)8,9 and a series of 8-[2-(4-aryl-
1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones (such as
prepared by acid-catalyzed cyclization of 38 which were them-
selves accessed from the corresponding 4-halo-3-methoxyaniline
by organolithiation and reaction with DMF followed by Wittig
reaction.12 The corresponding 3,4-dihydro-2(1H)-quinolinones
(6–9) were prepared similarly following an initial catalytic hydrog-
entation step on 38 (Scheme 3).
4,5)10 which had improved selectivity over hERG potassium chan-
nels (Fig. 1). This article reports additional SAR in the latter series
which has resulted in the identification of novel series of 5-{2-[4-
(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones
(10–24) and 3,4-dihydro-2(1H)-quinolinones (6–9) which possess
high 5-HT1A and 5-HT1D antagonist potencies with varying levels
of 5-HT1B and hSerT potencies. In addition, these compounds have
good levels of selectivity over hERG together with good rat PK
properties and thus represent interesting tool compounds to ex-
plore the therapeutic potential of different pharmacological pro-
files in a variety of disease indications.
The affinities of the compounds for the reuptake site of the
hSerT, stably expressed in epithelial pig kidney (LLCPK) cells, were
assessed by displacement of [3H]-citalopram binding by filtration
assay.13 The affinities of the compounds for hERG potassium chan-
nels, stably expressed in Chinese hamster ovary (CHO) cells, were
assessed by displacement of [3H]-dofetilide binding by proximity
assays.11 Compounds were screened against human-5-HT1A/B/D
receptors in a dose response GTPgS functional assay using Scintil-
lation Proximity Detection (LEADSeeker™) in both agonist and
antagonist mode, that is, in absence and presence of 5-HT, respec-
tively.11 Compounds with intrinsic activity (IA) in the agonist mode
P0.4 relative to 5-HT were classified as partial or full agonists and
only the agonist data is reported (pEC50) whereas compounds with
IA <0.4 in the agonist mode were classified as antagonists and data
from the antagonist mode is reported as a functional pKi (f-pKi).
Replacement of the oxygen in the benzoxazinone ring of 4 and 5
with methylene to afford the corresponding 3,4-dihydro-2(1H)-
quinolinones (6 and 7) maintained similar overall profiles with
very potent 5-HT1A/B/D antagonist potencies, good selectivity over
hERG and moderate hSerT potency in the case of the N-methyl ana-
log 7 (Table 1). Interestingly, the introduction of a methyl substitu-
ent (R2) into the 6-position (8 and 9) of the quinolinone ring
selectively reduced 5-HT1B potency affording potent 5-HT1A/D
antagonists along with modest hSerT potency. On further profiling
both these compounds demonstrated excellent rat PK properties
combining low blood clearance and good half-lives with good oral
bioavailability and brain exposure (Table 3).
The synthesis of the new compounds are shown in Schemes
1–3.11 The N-methylated 2(1H)-quinolinones (11, 19, 21 and 23)
and the N-H-2(1H)-quinolinone (10) were prepared starting from
the 5-quinolinol triflate 25 via two alternative synthetic approaches
(Scheme 1). The N-methyl analogs were accessed from 25 by Suzuki
coupling with allyltributylstannane followed by N-oxide formation
with mCPBA, trifluoroacetic anhydride (TFAA) mediated rearrange-
ment and N-methylation to afford 27. Oxidative cleavage of the pen-
dant vinyl with osmium tetraoxide followed by reductive amination
with the appropriate piperazinyl quinoline, completed the synthe-
sis. The N-unsubstituted 2(1H)-quinolinone (10) was also prepared
from 25 via the 5-quinolinone triflate 29. Heck coupling with
2-(ethenyloxy)-N,N-dimethylethanamine gave 30 which was
hydrolyzed under acidic conditions to the aldehyde 31 which was
converted into the desired final compound 10 by reductive amina-
tion as above.
The 6-methyl 2(1H)-quinolinones (12, 13, 16, 17, 20, 22 and 24)
were prepared according to the same general approaches as those
described in Scheme 1 starting from 5-bromo-6-methyl-2(1H)-
quinolinone (32) (Scheme 2). 5-Bromo-6-methyl-2(1H)-quinoli-
none (32) itself was prepared from 5-bromo-6-methylquinoline
by N-oxidation and TFAA mediated rearrangement as described
above.
Replacement of the CH2O in the benzoxazinone ring of 4 with
vinyl to afford the corresponding 2(1H)-quinolinone 10 maintained
a similar profile with very potent 5-HT1A/B/D antagonist potencies
combined with low to moderate hSerT potency but with signifi-
cantly reduced hERG binding affinity (Table 2). A similar result
was obtained in the case of the N-methyl analog 11 relative to
the corresponding benzoxazinone 5 although in this case some 5-
The 6-F and 6-Cl-2(1H)-quinolinone analogs (14 and 15) were
also prepared by the same route as described in Scheme 1 for 11
via the triflate derived from the corresponding 6-halo-5-meth-
oxy-2(1H)-quinolinone (42) (Scheme 3). Intermediates 42 were
N
N
N
O
N
O
i
ii, iii
iv
v
OTf
25
26
vi
27
28
O
vi
R1
ii, iii
N
H
N
O
O
R3
H
H
N
O
N
O
vii
viii
N
N
N
30
OTf
O
29
31
R4
O
N
10 R1 = H, R3 = H, R4 = H
11 R1 = Me, R3 = H, R4 = H
19 R1 = Me, R3 = S-Me, R4 = H
21 R1 = Me, R3 = S-Me, R4 = F
23 R1 = Me, R3 = di-Me, R4 = H
Scheme 1. Reagents and conditions: (i) allyltributylstannane, Pd(PPh3)4, LiCl, DMF, 100 °C, 1.5 h (95%); (ii) mCPBA, DCM, 0 °C, 2 h (100%); (iii) TFAA, DMF, 0 °C–rt, overnight
(85%); (iv) NaH, MeI, DMF, 0 °C–rt, 1 h (72%); (v) OsO4, NaIO4, THF/H2O (2:1), 10 min (65%); (vi) 7-R4-2-Me-5-(3-R3-1-piperazinyl)quinoline, NaBH(OAc)3, 1,2-DCE, rt, 6 h (39–
78%); (vii) 2-(ethenyloxy)-N,N-dimethylethanamine, Pd(OAc)2, PPh3, TEA, DMF, 100 °C, overnight (58%); (viii) H2SO4 (24%), DCM/pentane (4:1), rt, 4 h, (100%).

7094
S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7092–7096
H
H
H
N
N
O
N
O
O
v
vi
Br
32
33
34
O
O
iv
i
R1
N
N
O
R3
N
iv
N
O
N
O
N
O
ii
iii
X
Br
R4
35
36
37
O
N
12 R1 = H, R3 = H, R4 = H, X = N
13 R1 = Me, R3 = H, R4 = H, X = N
16 R1= Me, R3 = H, R4 = F, X = N
20 R1 = Me, R3 = S-Me, R4 = H, X = N
17 R1 = Me, R3 = R-Me, R4 = H, X = N
22 R1 = Me, R3 = S-Me, R4 = F, X = N
24 R1 = Me, R3 = H, R4 = H, X = CH
Scheme 2. Reagents and conditions: (i) NaH, MeI, DMF, 0 °C–rt, 1 h (67%); (ii) allyltributylstannane, Pd(PPh3)4, LiCl, DMF, 100 °C, 1.5 h (94%); (iii) OsO4, NaIO4, THF/H2O (2:1),
10 min (64%); (iv) 7-R4-2-Me-5-(3-R3-1-piperazinyl)quinoline, NaBH(OAc)3, 1,2-DCE, rt, 6 h (27–67%); (v) 2-(ethenyloxy)-N,N-dimethylethanamine, Pd(OAc)2, PPh3, TEA,
DMF, 100 °C, overnight (40%); (vi) H2SO4 (24%), DCM/pentane (4:1), rt, 4 h, (100%).
R1
R2
N
O
H
N
O
O
O
H
viii
N
O
iii, iv
v, vii
NH
i
NH ii
N
R2
R2
R2
R2
N
N
O
O
O
COOEt
O
COOEt
40
41
38 R2 = H, Me, Cl, F
39
6
8
R2= H, R1= H
ii
R2= Me, R1 =H
vi
R2
7
9
R2= H, R1= Me
N
R2= Me, R1 =Me
H
O
N
O
N
O
iii, iv
viii
N
R2
v, vi, vii
R2
N
14 R2= F
15 R2= Cl
O
42
43
O
N
Scheme 3. Reagents and conditions: (i) H2, Pd/C, EtOH, rt, 2 h (74–87%); (ii) HCl (10%), EtOH, reflux, overnight (59–63%); (iii) HBr (48% in H2O), 130 °C, 2.5 h (100%); (iv) 1,1,1-
trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]-methanesulfonamide, TEA, MeCN, rt, 7 h (73%); (v) allyltributylstannane, Pd(PPh3)4, LiCl, DMF, 100 °C, 1.5 h (62–89%); (vi)
NaH, MeI, DMF, 0 °C–rt, 1 h (53–68%); (vii) OsO4, NaIO4, THF/H2O (2:1), 10 min (52–64%); (viii) 2-Me-5-(1-piperazinyl)quinoline, NaBH(OAc)3, 1,2-DCE, rt, 6 h (36–55%).
HT1A/D partial agonism was apparent and the hSerT potency was
increased.
hERG affinity. The dimethyl analog 23 maintained good 5-HT1A/B
antagonist potencies with the highest level of hSerT potency yet
achieved in this series (Table 2).
Introducing a fluoro substituent into the 7-position of the quino-
line was also well tolerated (18, 21 and 22) and in the case of 21 had a
beneficial effect on hSerT relative to the corresponding unsubstitut-
ed analog 19. Combination of the substitutions described above gen-
erally had additive effects on SAR (17, 20 and 22). Replacement of the
piperazine ring of 13 with piperidine 24 led to a 10-fold increase in
hSerT and maintained 5-HT1A potency whilst increasing selectivity
Substitution of the 6-position (R2) of the quinolinone ring with
F, Cl, and Me (14, 15 and 16, respectively) was well tolerated in
terms of hSerT and 5-HT1A/D antagonist potencies (affording low
intrinsic activity) but selectively reduced 5-HT1B antagonist
potency. Further enhancements in hSerT potency were achieved
by introducing methyl substitution
a to the basic piperazine nitro-
gen (18–23). Whereas the R-enantiomer 18 had subnanomolar
hSerT and 5-HT1A/B/D antagonist potencies the S-enantiomer 19
demonstrated significantly reduced 5-HT1B activity and increased
over 5-HT1B and for the first time over 5-HT1D
.

S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7092–7096
7095
Table 1
a,b
Functional activity (f-pKi or pEC50
)
for human 5-HT1A/B/D receptors with intrinsic activity (IA) and SerT and hERG binding affinities (pKi)b: 5-{2-[4-(2-methyl-5-quinolinyl)-1-
piperazinyl]ethyl}-3,4-dihydro-2(1H)-quinolinones
R2
N
N
N
O
R1
X
N
*
a,b
Compdc
X
R1
R2
f-pKi or pEC50
pKib
5-HT1A (IA)
5-HT1B (IA)
5-HT1D (IA)
hSerT
hERG
4
5
6
7
8
9
O
O
CH2
CH2
CH2
CH2
H
Me
H
Me
H
Me
H
H
H
H
Me
Me
9.6 (0.0)
9.8 (0.0)
9.4 (0.3)
9.2 (0.0)
9.1 (0.0)
9.2 (0.0)
9.0 (0.0)
8.8 (0.0)
9.2 (0.0)
9.1 (0.0)
10.3 (0.0)
10.0 (0.0)
10.0 (0.0)
10.1 (0.0)
8.3 (0.5)
9.0 (0.0)
6.5
8.0
6.6
7.9
7.3
7.6
5.6
5.4
5.5
5.4
5.4
6.1
*
*
6.7 (0.4)
*
6.4 (0.4)
a
Data from the agonist mode (pEC50)* are reported for those compounds with intrinsic activity (IA) P 0.4 in this mode (i.e., partial or full agonists), whereas, for those
compounds with IA <0.4 in the agonist mode (i.e., antagonists) data from the antagonist mode is reported (f-pKi).
b
Each determination lies within 0.3 log units of the mean with a minimum of three replicates. See text for radioligands and assay details.
c
Compounds were characterized and purity assessed using 1H NMR and LCMS.
Table 2
Functional activity (f-pKi or pEC50
quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones
)
a,b for human 5-HT1A/B/D receptors with intrinsic activity (IA) and SerT and hERG binding affinities (pKi)b: 5-{2-[(2R)-2-methyl-4-(2-methyl-5-
R2
R4
R3
N
X
N
O
R1
N
*
a,b
Compdc
R1
R2
R3
R4
X
f-pKi or pEC50
pKib
5-HT1A (IA)
5-HT1B (IA)
5-HT1D (IA)
9.9 (0.0)
hSerT
hERG
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
H
Me
H
H
H
Me
Me
F
H
H
H
H
H
H
H
R-Me
R-Me
S-Me
S-Me
S-Me
S-Me
di-Me
H
H
H
H
H
H
H
F
H
F
H
H
F
N
N
N
N
N
N
N
N
N
N
N
N
N
N
CH
9.2 (0.0)
10.5 (0.4)
9.0 (0.0)
9.2 (0.0)
9.4 (0.0)
8.4 (0.0)
8.9 (0.0)
8.9 (0.0)
9.0 (0.0)
8.5 (0.0)
8.4 (0.0)
9.0 (0.0)
8.4 (0.0)
8.8 (0.3)
8.9 (0.0)
8.7 (0.0)
9.1 (0.0)
6.3 (0.4)
6.7
8.6
7.0
7.9
7.9
7.8
8.0
8.4
9.3
8.6
9.3
9.3
9.0
9.6
8.9
<4.5
5.0
4.6
5.4
4.5
5.3
5.6
5.1
5.0
5.3
5.8
5.2
5.9
5.6
5.7
*
9.0 (0.7)
*
*
8.6 (0.0)
8.7 (0.0)
9.4 (0.0)
8.4 (0.0)
8.7 (0.0)
8.6 (0.0)
9.9 (0.0)
8.3 (0.0)
7.7 (0.0)
8.9 (0.0)
<6.0
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
7.2 (0.4)
7.5 (0.0)
6.5 (0.5)
*
Cl
Me
Me
H
H
Me
H
Me
H
Me
<6.0
<6.0
9.1 (0.0)
6.4 (0.0)
<6.0
6.5 (0.0)
<6.0
F
H
H
<6.0
<6.0
9.3 (0.0)
7.4 (0.0)
a–c
See Table 1.
In an attempt to rationalize the observed SAR, a number of com-
by 24 at the 5-HT1B and 5-HT1D receptors might be related to the
greater steric hindrance of the Trp in 5-HT1B and 5-HT1D with
respect to Phe in 5-HT1A and contacts with the ECL2 residues pre-
venting 24 from favorably interacting with 5-HT1B and 5-HT1D
binding site residues.
In general all the quinolinones had low to moderate hERG
binding affinity suggesting low risk of potential QT effects
in vivo. On the basis of their interesting and varied pharmacolog-
ical profiles a range of analogs were tested in rat PK studies to ac-
cess their utility as biological tool compounds and potential for
further progression (Table 3). In general all the N-methylquinoli-
nones tested had good oral bioavailability (12–88%) moderate
clearance and moderate brain exposure based on brain to blood
ratios.
pounds were docked into the homology model of 5-HT1A receptor
previously built in house.9 In these models the primary interaction
of the compounds is with Asp13 on helix 3, which makes a charge
interaction with their tertiary amine moiety (Fig. 2). Another key
interaction involves the quinoline of the ligands and Trp20 in helix
6.14 The docking solutions obtained for 24 seem to suggest that the
methyl group at position 6 on the quinolone can be accommodated
near Phe9 in helix 3, which corresponds to a Trp in 5-HT1B and
5-HT1D receptors. Furthermore, this fragment is close to Ile10 in
helix 3 and to Asn8 in helix 7, which is replaced by a Thr in
5-HT1B and 5-HT1D receptors. Finally, this group is also close to
the ECL2 residues which are not conserved among the three recep-
tors. In light of these results, the reduced affinity/potency showed

7096
S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7092–7096
Figure 2. Docking of 24 in 5-HT1 receptor models.
2. Vaswani, M.; Linda, F. K.; Ramesh, S. Prog. Neuropsychopharmacol. Biol.
Table 3
Psychiatry 2003, 27, 85.
Rat pharmacokinetic profile for compounds 1–4, 13, 14 and 16
3. (a) Wood, M. D.; Thomas, D. R.; Watson, J. M. Expert Opin. Investig. Drugs 2002,
11, 457; (b) Blier, P.; De Montigny, C. Neuropsychopharmacology 1999, 21, 91S.
4. Beyer, C. E.; Boikess, S.; Luo, B.; Dawson, L. A. J. Psychopharmacol. 2002, 16, 297.
5. Roberts, C.; Price, G. W.; Middlemiss, D. N. Brain Res. Bull. 2001, 56, 463.
6. (a) Dawson, L. A.; Hughes, Z. A.; Watson, J. M.; Arban, R.; Price, G. W. Curr. Top.
Pharmacol. 2004, 8, 251; (b) Dawson, L. A.; Bromidge, S. M. Curr. Top. Med. Chem.
2008, 8, 1008.
7. (a) Atkinson, P. J.; Bromidge, S. M.; Duxon, M. S.; Gaster, L. M.; Hadley, M. S.;
Hammond, B.; Johnson, C. N.; Middlemiss, D. N.; North, S. E.; Price, G. W.; Rami,
H. K.; Riley, G. J.; Scott, C. M.; Shaw, T. E.; Starr, K. R.; Stemp, G.; Thewlis, K. M.;
Thomas, D. R.; Thompson, M.; Vong, A. K. K.; Watson, J. M. Bioorg. Med. Chem.
Lett. 2005, 15, 737; (b) Hughes, Z. A.; Starr, K. R.; Scott, C. M.; Newson, M. J.;
Sharp, T.; Watson, J. M.; Hagan, J. J.; Dawson, L. A. Psychopharmacology 2007,
192, 121; (c) Lovell, P. J.; Blaney, F. E.; Goodacre, C. J.; Scott, C. M.; Smith, P. W.;
Starr, K. R.; Thewlis, K. M.; Vong, A. K. K.; Ward, S. E.; Watson, J. M. Bioorg. Med.
Chem. Lett. 2007, 17, 1033; (d) Ward, S. E.; Johnson, C. N.; Lovell, P. J.; Scott, C.
M.; Smith, P. W.; Stemp, G.; Thewlis, K. M.; Vong, A. K.; Watson, J. M. Bioorg.
Med. Chem. Lett. 2007, 17, 5214.
Compd
Cli rat; huma
liver (ml/min/g)
CLbb
(ml/min/kg)
Vss
(L/kg)
t
(h)
Fpo %
Br:Bl
½
4
5
8
9
11
13
16
17
19
20
21
23
24
0.7; 1.0
1.0; 2.4
<0.5; <0.5
1.6; 1.3
0.8; 1.2
2.2; 1.5
2.3; 1.6
3.8; 1.2
0.7; 1.5
1.9; <0.5
0.7; 0.8
8.0; 3.8
2.0; 0.9
8
29
7
3.4
1.7
3.0
2.0
2.1
2.3
2.4
2.1
1.2
2.7
2.0
0.8
3.4
5.2
1.0
5.4
3.0
1.3
1.1
0.7
1.5
0.6
1.2
1.6
0.6
1.4
63
26
73
83
37
88
82
31
12
35
34
27
82
0.7
1.5
0.8
0.4
1.1
0.5
ND
0.4
1.3
1.7
1.2
1.1
0.8
9
32
28
46
21
32
46
34
34
31
a
8. Serafinowska, H. T.; Blaney, F. E.; Lovell, P. J.; Merlo, G.; Scott, C. M.; Smith, P.
W.; Starr, K. R.; Watson, J. M. Bioorg. Med. Chem. Lett. 2008, 18, 5581.
9. Bromidge, S. M.; Bertani, B.; Borriello, M.; Faedo, S.; Gordon, L. J.; Granci, E.;
Hill, M.; Marshall, H. R.; Stasi, L. P.; Zucchelli, V.; Merlo, G.; Vesentini, A.;
Watson, J. M.; Zonzini, L. Bioorg. Med. Chem. Lett. 2008, 18, 5653.
10. Bromidge, S. M.; Bertani, B.; Borriello, M.; Bozzoli, A.; Faedo, S.; Gianotti, M.;
Gordon, L. J.; Hill, M.; Zucchelli, V.; Watson, J. M.; Zonzini, L. Bioorg. Med. Chem.
Lett. 2009, 19, 2338.
11. Bertani, B.; Bromidge, S. M.; Gianotti, M.; Pasquarello, A.; Zucchelli, V. WO
Patent 200,80,37,681 2008.
12. Tamura, Y.; Chen, L. C.; Fujita, M.; Kita, Y. Chem. Pharm. Bull. 1982, 30, 1257.
13. Bertani, B.; Borriello, M.; Bozzoli, A.; Bromidge, S. M.; Granci, E.; Leslie, C.;
Serafinowska, H.; Stasi, L.; Vong, A.; Zucchelli, V. WO Patent 200,40,46,124
2004.
Intrinsic clearance in liver microsomes.
In vivo data determined by 0.5 mg/kg iv and 1 mg/kg po administration in rat.
b
Thus 3,4-dihydro-2(1H)-quinolinones and 2(1H)-quinolinones
(6–24) have been identified with a range of different pharmacolog-
ical profiles at hSerT and 5-HT1 autoreceptors combined with good
rat PK properties. The availability of tool compounds with a range
of profiles at targets known to play a key role in the control of syn-
aptic 5-HT levels will allow the exploration of different permuta-
tions of activity in a variety of animal behavioral and disease
models. The results of these studies and the further optimization
of these series will be reported in due course.
14. The 3D structure of 24 was generated starting from its Daylight SMILE which
was converted into SD 2D file format with the use of smi2mol Daylight routine
and then transformed into SD 3D with the use of Corina [Accelrys]. ESP charges
were calculated with the use of MOPAC 6.0 [available within Sybyl, Tripos].
Docking experiments were carried out within the receptor substructure
defined by the residues lying within a 15 Å radius sphere centred on Asp13
in helix 3. Coordinates were allowed to change upon energy minimization. The
remaining receptor model residues surrounding the previous ones were kept
rigidly frozen in place throughout all the simulations. 24 was manually docked
in the binding site described above and the energy of the complex obtained
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.09.085.
*
was minimized with the use of AMBER force field as implemented in
References and notes
Batchmin V9.1 [Schrodinger], distance dependent electrostatic model (e = 2r),
VDW cut-off = 7 Å, electrostatic cut-off = 20 Å, charges from structure file. 10K
steps of PR Conjugate Gradient (PRCG) were used to minimize the complex;
convergence was set on gradient (0.05 kJ molÀ1 ÅÀ1).
1. (a) Hirschfeld, R. M. A. J. Clin. Psychiatry 2000, 61, 4; (b) Lucki, I. Biol. Psychiatry
1998, 44, 151; (c) Naughton, M.; Mulrooney, J. B.; Leonard, B. E. Hum.
Psychopharmacol. 2000, 15, 397.