Studies on a series of potent, orally bioavailable, 5-HT1 receptor ligands-Part II

Article abstract of DOI:10.1016/j.bmcl.2008.11.052

A series of 5-(piperidinylethyloxy)quinoline 5-HT₁ receptor ligands have been studied by elaboration of the series of dual 5-HT₁-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT_1A, 5-HT_1B and 5-HT_1D receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.

Full text of DOI:10.1016/j.bmcl.2008.11.052

Bioorganic & Medicinal Chemistry Letters 19 (2009) 428–432
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Studies on a series of potent, orally bioavailable, 5-HT1 receptor ligands—Part II
*
Simon E. Ward , Peter Eddershaw, Sean T. Flynn, Laurie Gordon, Peter J. Lovell, Susan H. Moore,
Claire M. Scott, Paul W. Smith, Kevin M. Thewlis, Paul A. Wyman
Neuroscience Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 5-(piperidinylethyloxy)quinoline 5-HT1 receptor ligands have been studied by elaboration of
the series of dual 5-HT1-SSRIs reported previously. These new compounds display a different in vitro
pharmacological profile with potent affinity across the 5-HT1A, 5-HT1B and 5-HT1D receptors and selectiv-
ity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS
penetration.
Received 21 October 2008
Revised 13 November 2008
Accepted 14 November 2008
Available online 19 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
5-HT1
SSRI
Serotonin
5-HT1A antagonist
Depression
Antidepressants are thought to mediate their effects by improv-
ing 5-HT transmission, regardless of their modes of action. Selec-
tive serotonin reuptake inhibitors (SSRIs) block 5-HT reuptake
mediated by the 5-HT transporter (SerT) located in 5-HT neuron
terminals and cell bodies. SSRIs have been shown to be effective
in the treatment of both depression and anxiety disorders. Com-
pared to other antidepressants, such as tricyclics, they offer similar
efficacy but with an improved side effect profile. However, there is
still a medical need for the development of molecules with a supe-
rior profile to SSRIs by providing a faster onset of action and better
tolerability with respect to the sleep disturbance and sexual dys-
function side effects associated with current SSRIs.1
The rationale for the delay to onset of antidepressant action has
been the subject of considerable debate. A widely accepted view is
that a neuro-adaptive process occurs as a result of constant inhibi-
tion of the monoamine reuptake process, presumably through
desensitisation of presynaptic 5-HT1A receptors located on the cell
bodies which control cell firing and the consequent release of 5-HT
from presynaptic neurons of the dorsal raphe.2 Two other receptors
play an important role in the control of 5-HT release from presyn-
aptic neurons, the 5-HT1B and 5-HT1D autoreceptors located on the
5-HT cell bodies and on the nerve terminals, and pre-clinical evi-
dence suggests that chronic administration of antidepressants
leads to desensitisation of the 5-HT1B autoreceptors. Thus, the
simultaneous blockade of the 5-HT1A, 5-HT1B and 5-HT1D autore-
ceptors should restore post-synaptic 5-HT neuronal transmission
and so provide a complementary approach to the SSRI or mixed
SSRI/5-HT1A receptor antagonist strategies.3
Previous publications from our laboratories in this chemical
series have described a range of pharmacological profiles across
the 5-HT1 receptors and 5-HT transporter. Modification of the ben-
zoxazinone group has allowed identification of selective 5-HT1D
antagonists,4 mixed 5-HT1A antagonist/SSRIs5 and 5-HT1ABD antag-
onists.6 In particular, later studies have focussed on the identification
of molecules which are potent, selective 5-HT1 receptor ligands, that
is molecules with pKi > 8 against the 5-HT1A, 5-HT1B and 5-HT1D
receptors with low intrinsic activity and good selectivity over other
receptors and transporters, including the 5-HT transporter.
The preceding report from these studies identified the first
compounds to meet this target profile (Fig. 1).5 However, during
the course of this SAR investigation, we routinely struggled to meet
the required pKi for all three of the 5-HT1 receptor subtypes. In par-
ticular, few compounds achieved a pKi > 8 for the 5-HT1B receptor,
which encouraged us to focus our efforts specifically on identifica-
tion of new, potent antagonists for this receptor.
In earlier published work we described the identification of
selective 5-HT1B receptor antagonists exemplified by SB-616234
(Fig. 2).7 Here, the piperazine and its substituents were key to high
5-HT1B receptor affinity. In our previous series of 5-HT1 receptor
antagonists, basic centres were also tolerated as a substituent at
the 3-position of the phenyl group (1).6 This paper now describes
a further investigation around substituents at the 3-position,
including a range of substituted piperazines.
Previous SAR activity indicated that an H-bond acceptor in the
meta position of the phenyl group was key for affinity, as exemplified
* Corresponding author. Tel.: +44 1279 622894; fax: +44 1279 627728.
E-mail address: simon.e.ward@gsk.com (S.E. Ward).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.11.052

S. E. Ward et al. / Bioorg. Med. Chem. Lett. 19 (2009) 428–432
429
H
N
H
N
SO2Me
N
N
O
N
O
N
O
N
2
1
Figure 1. Examples of potent analogues from previous studies with basic and non-basic phenyl substituents.
N
removed from 3 to give 4 with no change in receptor profile.
However, removal of the alternative methyl from 3 to give the
piperazine with the opposite stereochemistry 5 led to a drop in
affinity for the 5-HT1B receptor. A similar drop in affinity was
observed by introducing another methyl substituent to 4 to give
dimethyl piperazine 6. This work was then carried further to look
at simplification of the structure to afford achiral piperazine 7.
Pleasingly, this change again gave us a compound which met all
target criteria for the 5-HT1 receptors without the need for addi-
tional chiral centres.
On this simpler template, we then investigated the electronic
nature of the piperazine nitrogens. Piperazinone derivatives 8
and 9 were prepared to investigate the difference in binding affin-
ity between amide and amine environments. Both molecules
showed a loss in receptor binding affinity—the terminal nitrogen
as an amide was less potent than as a basic amine, and piperazi-
none 9 (Scheme 2), was less potent both than parent piperazine
and than its unconstrained beta amino amide analogue 1.
Data for compound 8 was corroborated by replacement of the
basic nitrogen with oxygen, that is, another non-basic, polar group,
giving 11. This modification led to a drop in 5-HT1B receptor affin-
ity which could not be restored by introducing flanking methyl
groups to afford 12.
However, we were surprised to discover that replacement of the
piperazine with a piperidine to give analogue 10 was not detri-
mental to binding affinities and gave a slightly improved 5-HT1B
affinity compared to initial piperazine 7. This was the first mole-
cule to maintain high receptor affinities which lacked either an
aniline amide or sulfonamide unit or the terminal basic nitrogen,
although microsomal clearance increased from 2.9 ml/min/kg (7)
to 6.2 ml/min/kg (10). Varying the size of this piperidine ring to
pyrrolidine analogue 14 led to a drop in affinities whilst the homo
piperazine 13 maintained the receptor profile, but led to greater
microsomal instability (rat CLi 26 ml/min/kg).
O
N
O
NH
N
O
N
Figure 2. Structure of SB-616234, a selective 5-HT1B receptor antagonist.
by 2 above; aniline derivatives lacking the carbonyl or sulfonyl
group showed considerably reduced 5-HT1B and 5-HT1D receptor
affinities.
Nonetheless, our first target was to incorporate the piperazine
substituent present in SB-616234 into our series. This compound
and its analogues were prepared (Scheme 1a) from 3-bromoben-
zylbromide 23 via Horner–Wadsworth–Emmons coupling to give
intermediate 24, which following deprotection to amine 25 was
coupled to the quinoline fragment 264 via alkylation. The key
unsaturated bromophenyl derivative 27 was reacted under palla-
dium (0) catalysis using Buchwald conditions to give intermediates
28 (Cy = cyclic amine). These compounds were then reduced to
give the final molecules screened 29 (3–8, 10–14).
Data displayed in Table 1 are for the molecules screened against
h5-HT1A receptors expressed in CHO cells using displacement of
[3H]-WAY100635 and against h5-HT1B and h5-HT1D receptors ex-
pressed in CHO cells using displacement of [3H]-5-HT. The intrinsic
activity of the compounds was determined using a [35S]GTP
cS
binding assay in cells expressing the h5-HT1A
, h5-HT1B or
h5-HT1D receptors, with data reported relative to the maximum re-
sponse elicited by the endogenous agonist 5-HT. A ten point half
serial dilution was used to generate a concentration response for
each compound.
Gratifyingly, the direct analogue 3, not only gave us the desired
high affinity for the 5-HT1B receptor, but also high affinity for the
5-HT1A and 5-HT1D receptors. Investigation of the effect of the
methyl group substitution pattern and stereochemistry led to the
preparation of 4–6. One of the methyl substituents could be
To further test the requirement of the meta nitrogen substituent
on the phenyl ring, we decided to synthesise compound 15. This
piperidine derivative was prepared (Scheme 3) from the pyridyl
Et O
Br
Br
iii
Br
Br
ii
i
Br
P
Et O
N
N
O
tBoc
Br
H
23
24
25
Br
Cy
O
v or vi
iv
N
N
O
O
N
N
N
28
Cy = cyclic amine (1a) or aryl (1b)
27
26
Cy
vii
N
O
N
29
Scheme 1a (Buchwald) and 1b (Suzuki). Reagents and conditions: (i) P(OEt)3, toluene, reflux, 24 h, (85%); (ii) N-Boc-piperid-4-one, NaH, THF, rt, 4 h (89%); (iii) 1 M HCl in
Et2O, rt, 72 h (57%); (iv) 25, K2CO3, DMF, 100 °C, 16 h, 87%; (v) amine, Pd(OAc)2, BINAP, Cs2CO3, 1,4-dioxane, reflux (39–100%); (vi) CyB(OH)2, PPh3, 2 M aq K2CO3, Pd(OAc)2,
reflux, 1,2-DME; (vii) 10% Pd on C, H2, EtOH, rt, 24 h, (9–100%).

430
S. E. Ward et al. / Bioorg. Med. Chem. Lett. 19 (2009) 428–432
Table 1
Receptor binding affinity (pKia) for 5-HT1A, 5-HT1B, 5-HT1D and SerT for novel compoundsb
X
N
O
N
Compound
X
pKi
I.A.c
pKi
I.A.c
pKi
I.A.c
SerTd
Synthesis
1
2
NHCOCH2NMe2
7.8
8.6
inv
0
8.2
8.7
0.2
0.3
9.0
9.3
0.4
0
6.4
6.0
NHSO2Me
Me
3
4
8.7
8.6
0
0
8.4
8.7
0.3
0.3
9.1
9.2
0.5
0.5
ND
6.2
Scheme 1a
Scheme 1a
NH
N
Me
Me
NH
N
Me
5
6
8.4
8.3
0
7.8
7.5
0.3
ND
9.0
9.0
0.5
ND
6.1
6.1
Scheme 1a
Scheme 1a
NH
N
Me
NH
N
ND
Me
Me
N
7
8
9.0
8.1
7.7
8.4
8.3
8.6
0
8.2
6.9
7.2
8.7
6.9
6.8
0.3
ND
ND
0.6
0.4
ND
9.3
8.0
8.4
9.0
8.6
8.8
0.4
ND
ND
0.7
0.6
ND
ND
ND
ND
6.8
6.6
6.6
Scheme 1a
Scheme 1a
Scheme 2
Scheme 1a
Scheme 1a
Scheme 1a
N
O
Me
N
ND
ND
0
N
O
N
9
N
N
10
11
12
O
0
N
ND
O
N
N
13
14
15
16
17
18
19
20
8.6
8.0
8.5
8.2
7.9
8.1
8.1
8.3
0
8.1
7.4
8.3
8.2
6.8
7.1
8.1
7.9
0.3
ND
0.3
ND
ND
ND
ND
ND
9.2
8.6
9.7
8.9
8.4
8.5
9.0
8.7
0.5
ND
0.4
ND
ND
ND
ND
ND
6.4
ND
6.3
ND
ND
ND
ND
ND
Scheme 1a
Scheme 1a
Scheme 3
Scheme 3
Scheme 3
Scheme 3
Scheme 1b
Scheme 1b
N
ND
inv
ND
ND
ND
ND
ND
N
N
NH
Ac
N
SO Me
2
N
N
N
(continued on next page)

S. E. Ward et al. / Bioorg. Med. Chem. Lett. 19 (2009) 428–432
431
Table 1 (continued)
Compound
X
pKi
I.A.c
ND
pKi
I.A.c
ND
pKi
I.A.c
ND
SerTd
ND
Synthesis
21
22
7.2
7.2
8.1
Scheme 1b
Scheme 1b
O
7.5
ND
7.4
ND
8.2
ND
ND
ND, not determined.
a
Radioligand binding assay to determine affinity at human recombinant 5-HT receptors. Each determination lies within 0.3 log units of the mean with a minimum of three
replicates.
b
c
All compounds were characterized and purity was assessed using 1H NMR and LCMS.
I.A., intrinsic activity (inv, inverse agonist).
d
Functional 3[H]5-HT uptake assay in at cortical synaptosomes.
H
N
NH2
OH
N
N
N
iii, iv
i, ii
N
N
O
N
O
N
O
N
O
N
O
9
Scheme 2. Reagents and conditions: (i) chloroacetylchloride, Et3N, rt, DCM; (ii) MeNCH2CH2OH, iPr2NEt, NaI, rt, iPrOH; (iii) ClSO2Me, Pyr, rt; (iv) NaH, DMF, rt to 50 °C, 22%
over entire sequence.
intermediate 31 via quaternisation and global reduction to N-methyl
piperidyl 32. Standard elaboration of this intermediate gave 15.
In stark contrast to all previous findings,5,6 we saw high recep-
tor binding affinity for compound 15 with low intrinsic activity.
This clearly demonstrated that although we had discovered that
the piperazine substituent could be used as an alternative to the
3-amido/sulfonamido derivatives such as 2 to give us high 5-HT1
receptor binding affinity, either nitrogen could be replaced by a
methylene unit with no adverse impact on the receptor binding
profile, despite the difference in nitrogen basicity and polarity.
This piperidine 15 then allowed us to envisage a set of ana-
logues exploring different receptor and physicochemical space to
those previously prepared, with the hope of being able to modulate
the overall properties of the molecule to a greater degree than
hitherto possible. Examination of the nature of the basic nitrogen
in the piperidine showed that moving from the tertiary to second-
ary amine in 16 had a minimal impact on the affinities, but
attempts to then derivatise the amine further into amide 17 or
sulfonamide 18 led to a decrease in receptor binding affinity.
Given the data described, we reasoned that we should be able to
replace the 3-phenyl substituent with an aromatic group. These
analogues were prepared using similar methodology to the piper-
azines above using Suzuki coupling conditions to install the aryl
groups (Scheme 1b, Cy = aryl). The activity of piperidine 15 led
us to initially examine pyridine 19, which gratifyingly maintained
good receptor affinity across the compound set. In keeping with
previous observations that the terminal nitrogen was not key to
high affinity, the pyridine regioisomer 20 also showed a good pro-
file. Further extension of this principle to removal of all heteroat-
oms to afford phenyl derivative 21 led to an unacceptable drop
in binding affinities which could not be restored by reintroduction
of a heteroatom in the 5-membered system to give furan 22.
In line with earlier observations,6 and that reported for 1 and 2,
low activity against the serotonin transporter was observed for all
+
N
N
Br
ii
iii
i
N
tBoc
N
N
tBoc
tBoc
31
24
N
N
N
v
iv
N
N
O
N
HN
tBoc
15
32
R
NH
N
vii
vi
N
N
N
O
N
O
17 R = A c
18 R = SO2Me
16
Scheme 3. Reagents and conditions: (i) 4-pyridyl boronic acid, Pd(Ph3)4, Na2CO3, H2O/DME, reflux, 54%; (ii) MeI, DCM, rt, 95%; (iii) Pt2O, H2, EtOH, 50 °C, 88%; (iv) HCl, Et2O, rt,
i
100%; (v) 26, K2CO3, DMF, 100 °C, 16 h, 40%; (vi) ClO2CCHClCH3, Pr2NEt, 1,2-dichloroethane, reflux, 62%; (vii) for R = Ac; Ac2O, Pyr, DCM, rt, 61%; for R = SO2Me, MeSO2Cl,
iPr2NEt, NEt3, DCM, rt, 70%.

432
S. E. Ward et al. / Bioorg. Med. Chem. Lett. 19 (2009) 428–432
Table 2
in compound 15 having a significantly longer half-life in blood
than compound 7 and also than the compounds previously de-
scribed.5 Both compounds showed evidence of CNS penetration.
More detailed characterisation of these analogues including the
use of 15 as a potential in vivo tool is on-going.
Pharmacokinetic profiles of piperazine and piperidine analogues in rat
b
c
Compound CLi (ml/min/g) CLb
t½
CNS br:blb Vss
(L/kg) (ng/g)
Brain Cmax
human/rata
(ml/min/kg)b (h)
7
15
h 1.6; r 2.9
h < 0.5; r 2.0
46
14
1.3 18
12 1.3
4.4
12.4
85
34
a
Intrinsic clearance determined in microsomes.
In vivo data determined by 1 mg/kg iv study in rat.
Brain Cmax and brain:blood ratio determined by additional 3 mg/kg oral rat PK
References and notes
b
c
1. Hirschfeld, R. M. J. Clin. Psychiatry 2000, 61, 4.
study (br:bl from whole brain AUC concentration measurements).
2. de Montigny, C.; Blier, P.; Chaput, Y. Neuropharmacology 1984, 23, 1511.
3. Roberts, C.; Price, G. W.; Middlemiss, D. N. Brain Res. Bull. 2001, 56, 463.
4. Ward, S. E.; Harrington, F. P.; Gordon, L. J.; Hopley, S. C.; Scott, C. M.; Watson, J.
M. J. Med. Chem. 2005, 48, 3478.
5. 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.
6. Ward, S. E.; Eddershaw, P. J.; Scott, C. M.; Gordon, L. J.; Lovell, P. J.; Moore, S. H.;
Smith, P. W.; Starr, K. R.; Thewlis, K. M.; Watson, J. M. J. Med. Chem. 2008, 51,
2887.
compounds profiled, often leading to greater than 100-fold selec-
tivity for the 5-HT1 receptors. A number of these compounds were
profiled further, and pharmacokinetic data are presented for piper-
azine 7 and piperidine 15 (Table 2). Both are dibasic compounds;
though compound 15 which contains two basic piperidine units
showed an appreciably higher volume of distribution than the less
basic compound 7. This, coupled with its lower clearance resulted
7. Wyman, P. A.; Marshall, H. R.; Flynn, S. T.; King, R. J.; Thompson, M.; Smith, P.
W.; Hadley, M. S.; Price, G. W.; Scott, C. M.; Dawson, L. A. Bioorg. Med. Chem. Lett.
2005, 15, 4708.