Aminoalkyl phenyl sulfones - A novel series of 5-HT7 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2005.11.067

A novel series of 5-HT₇ receptor ligands has been identified and evaluated, providing compounds showing a broad spectrum of functional activities and good selectivity over selected receptors and ion channels.

Full text of DOI:10.1016/j.bmcl.2005.11.067

Bioorganic & Medicinal Chemistry Letters 16 (2006) 1255–1258
Aminoalkyl phenyl sulfones—a novel series
of 5-HT7 receptor ligands
Piotr Raubo,* Margaret S. Beer, Peter A. Hunt, Ian T. Huscroft, Clare London,
Josephine A. Stanton and Janusz J. Kulagowski
The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20 2QR, UK
Received 2 November 2005; revised 17 November 2005; accepted 18 November 2005
Available online 7 December 2005
Abstract—A novel series of 5-HT7 receptor ligands has been identified and evaluated, providing compounds showing a broad spec-
trum of functional activities and good selectivity over selected receptors and ion channels.
Ó 2005 Elsevier Ltd. All rights reserved.
The human 5-HT7 receptor is the most recently discov-
ered subtype of the serotonin receptor family.1 The bio-
N
N
logical functions of this receptor are not well
understood, but recent reports suggest that 5-HT7 recep-
tors may be implicated in a variety of physiological and
pathophysiological processes such as cognition,2 schizo-
phrenia,3 migraine,4 regulation of circadian rhythm,5
epilepsy6 and in the aetiology of depression.7
N
H
N
S O
O
O
N
H
SB-656104
DR4004
NH2
N
N
N
N
N
OPh
H
N
N
N
H
Me
H
H
The development of selective agonists and antagonists
would greatly facilitate determination of the actual role
of the 5-HT7 receptor. Recently, a number of structural-
ly diverse 5-HT7 receptor ligands have been disclosed8
(e.g., SB-656104, DR4004, 1 and 2; Fig. 1).
1
2
Figure 1.
As part of our 5-HT7 receptor programme, we were
interested in the identification of new, structurally di-
verse chemical classes of selective 5-HT7 receptor ligands
that could be used for in vivo studies of 5-HT7 receptor
function. Here, we report the aminoalkyl phenyl sulf-
ones as a new class of 5-HT7 receptor ligands.
Preliminary modelling studies suggested that a gem-di-
substituted cyclobutyl sulfone derivative 3 could overlay
with one of the low-energy conformations of SB-269970
(Fig. 2). SB-269970 was subjected to a torsion search
and the resulting conformers were minimised with
the MMFF94 forcefield implemented within SYBYL.
Keywords: 5-HT7 receptor; Selective ligands; Antagonist; Agonist;
Sulfones.
Figure 2. Molecular overlay of structures 3 (black) and SB-269970
(green).
*
Corresponding author. E-mail: piotr_raubo@merck.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.11.067

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P. Raubo et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1255–1258
Conformers that were within 5 kcal of the minimum
were examined, and the most favoured was used as the
starting point for the modelling of the cyclobutyl deriv-
ative 3. Once constructed the derivative 3 was also mini-
mised using the MMFF94 forcefield and overlaid with
the starting sulfonamide template as shown in Figure 2.
Scheme 3. Reagents: (i) NH(OMe)Me hydrochloride, i-PrMgCl, THF,
98%; (ii) DIBAL-H (1.6 equiv), DCM, 99%; (iii) TOSMICÒ, K2CO3,
MeOH.
A series of cyclobutyl sulfones was prepared from 4 as
outlined (Scheme 1). The cyclobutyl ring was installed
via dialkylation of the bis-sulfone 4 with 1,3-dibromopro-
pane under phase-transfer catalysis. Mono desulfonyla-
tion of 5 using 1 equiv of lithium naphthalenide
followed by alkylation with the appropriate dibromoal-
kane provided the bromide 6, a key intermediate for the
synthesis of the desired amino sulfones (8). When 1,2-dib-
romoethane was used, spontaneous b-elimination of HBr
occurred, giving the olefin 7. Thus, an alternative protocol
involving hydroboration–oxidation of the double bond in
7 was applied providing 8 (n = 0) in three steps.
Table 1. 5-HT7 receptor binding affinity of cyclobutyl sulfones 8
Compound
NR1R2
n
5-HT7 (Ki/nM)10
8a
1
>7000
8b
8c
1
1
1
1
1
1
1
1
0
2
2700
>7000
550
5800
22
The 4-bromobutyl phenyl sulfone9 9 was used for prepa-
ration of 11 (Scheme 2). gem-Dimethyl sulfone 10 was
prepared by alkylation of lithiated isopropyl phenyl sul-
fone with 1,3-dibromopropane and this product was cou-
pled with appropriate amines to produce the series 12.
8d
8e
8f
The oxazole ring in 12f was constructed by a three-step
sequence beginning with conversion of 12a to the Wein-
reb amide, followed by reduction to the corresponding
aldehyde which underwent reaction with TOSMICÒ
(Scheme 3).
8g
8h
8ia
8ja
8ka
26
8
9
A structure–activity relationship (SAR) study on com-
pounds of generic structure 8 initially focussed on vary-
ing the amine fragment and length of the alkyl chain
(Table 1).
53
13
Values represent the geometric mean of 2–5 determinations.
a Racemate.
Table 2. Receptor binding selectivity and functional profile of sulfones
Compound NR1R2
5-HT7
5-HT1A
5-HT2A
5-CT
(Ki/nM)10 (Ki/nM)12 (Ki/nM)13 (%)11
8h
8
6
35
65
5
8la
210
570
39
11a
96
8
NT
NT
NT
83
Scheme 1. Reagents: (i) NaOH, Br(CH2)3Br, n-Bu4NBr, DCM, H2O,
71%; (ii) lithium naphthalenide, then Br(CH2)n+2Br, THF, 28–65%;
(iii) BH3–THF complex, THF, then H2O2, NaOH, 23%; (iv) MsCl,
Et3N, DCM, 58%; (v) HNR1R2, K2CO3, MeCN, 70–95%.
12ba
1500
2000
Values represent the geometric mean of 2–5 determinations. NT = not
tested.
a Racemate.
Thus, a range of amines, that included substituted piper-
azine, and piperidine analogues, were prepared and
tested in a 5-HT7 receptor binding assay. A dramatic
Scheme 2. Reagents: (i) HNR1R2, K2CO3, MeCN, 70–95%.

P. Raubo et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1255–1258
Table 3. Receptor binding selectivity and functional profile of sulfones 12
1257
Compound
NR1R2
5-HT7
(Ki/nM)10
5-HT1A
(Ki/nM)12
5-HT1B
(Ki/nM)14
5-HT2A
(Ki/nM)13
D2
(Ki/nM)15
a1
hERG
(Ki/nM)17
5-CT (%)11
(Ki/nM)16
12ba
8
54
24
455
15
7
1500
>7000
2400
NT
>7000
>7000
>7000
NT
2000
>2000
1870
900
>1000
710
3900
>4000
>4000
NT
>4000
>5000
>5000
NT
83
0
12ca
12d
0
12e
NT
NT
NT
12
0
12fa
12ga
>7000
400
>5000
7700
>1000
1800
1500
220
>4000
540
>8000
>5000
Values represent the geometric mean of 2–5 determinations. NT = not tested.
a Racemate.
improvement in binding affinity was observed with pen-
dant aromatic groups at the 4-position of piperazine (8f)
or piperidine (8g) rings as well as with 1,2,3,4-tetrahy-
droisoquinoline (8h). The three-carbon linker (n = 1)
was chosen for further SAR evaluation.
In conclusion, a novel series of 5-HT7 receptor ligands
was identified and evaluated, providing compounds
showing a broad spectrum of functional activities and
good selectivity over selected receptors and ion
channels.
1,2,3,4-Tetrahydroisoquinoline derivative 8h was count-
erscreened against selected serotonergic (h5-HT1A and
h5-HT2A) receptors (Table 2) and showed modest 4- to
8-fold selectivity.
Acknowledgments
The authors thank F. Pelaez, M. Mojena, M. Maroto
and A. Cabello at Merck, Sharp and Dohme, CIBE
(Spain) for counterscreening results.
This compound was also evaluated in a functional mod-
el of 5-HT7 receptor activation11 and found to behave as
an antagonist, giving 5% of the response of the full ago-
nist 5-carboxamidotryptamine (5-CT) at 10 lM concen-
tration. A notable improvement in selectivity was
observed when 1,2,3,4-tetrahydroisoquinoline was re-
placed with trans-perhydroisoquinoline providing 8l.
The sulfone 11 having no substituent at the position a
to the sulfonyl group was 16-fold less potent than 8l in
inhibiting [3H]-5-HT binding to the human 5-HT7 recep-
tor. Introduction of gem-dimethyl substitution at the a-
position to afford 12b resulted in a compound with an
excellent selectivity profile (>100-fold) over those of
receptors tested, as indicated in Table 3. However, 12b
was found to behave as a partial agonist, giving 83%
of the response of 5-CT at h5-HT7 receptors. Evaluation
of amine SAR in the gem-dimethyl series demonstrated
that functional activity can be attenuated by installing a
pendant substituent at the 3-position, as exemplified by
12c–g (Table 3). This was accomplished without diminu-
tion of the selectivity profile. A variety of substituents
were tolerated in the 3-position. The R ester 12d was
found to be 19-fold more potent than the S enantiomer
(12e) at inhibiting [3H]-5-HT binding to the human 5-
HT7 receptor. Sulfones 12d and 12f exhibited high affin-
ity at the human 5-HT7 receptor with minimal or no
functional activity and >30-fold selectivity over selected
receptors and ion channels.
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