Studies towards the identification of a new generation of atypical antipsychotic agents

Article abstract of DOI:10.1016/j.bmcl.2006.10.036

A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D₂/D₃ receptor antagonism with serotonin 5

Full text of DOI:10.1016/j.bmcl.2006.10.036

Bioorganic & Medicinal Chemistry Letters 17 (2007) 400–405
Studies towards the identification of a new generation of
atypical antipsychotic agents
Vincenzo Garzya,a,* Ian T. Forbes,a Andrew D. Gribble,a Mike S. Hadley,a
Andrew P. Lightfoot,a Andrew H. Payne,a Alexander B. Smith,a Sara E. Douglas,a
David G. Cooper,a Ian G. Stansfield,a Malcom Meeson,a Emma E. Dodds,a
Declan N. C. Jones,a Martyn Wood,a Charlie Reavill,a Carol A. Scorer,a
Angela Worby,b Graham Riley,b Peter Eddershaw,a Chris Ioannou,a Daniele Donati,c
Jim J. Hagana and Emiliangelo A. Rattic
aPsychiatry Centre of Excellence for Drug Discovery, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK
bDiscovery Research GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK
cMedicine Research Centre Via Alessandro Fleming 4, 37135 Verona, Italy
Received 2 August 2006; revised 15 October 2006; accepted 16 October 2006
Available online 19 October 2006
Abstract—A rational structure–activity relationship study around compound (1) is reported. The lead optimisation programme led
to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A
,
5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required
in vivo activity with no EPS liability.
Ó 2006 Elsevier Ltd. All rights reserved.
Schizophrenia is a severe psychiatric disorder affecting
approximately 1.5% of the world population.1 Diagnos-
tic features of schizophrenia include positive symptoms
(auditory hallucinations, disorganised thoughts and
delusions), negative symptoms (social withdrawal, lack
of motivation) and cognitive dysfunction (disorganised
thinking, memory impairments).2 One of the conse-
quences of this debilitating illness is the high rate of sui-
cide in patients affected by the disease.3
synaptic dopamine D2 receptors. Unfortunately, nega-
tive symptoms and cognitive impairment are not fully
addressed by these two classes of drugs. Additionally,
their broad receptor interaction profiles (affinities at
up to 15 different neurotransmitter receptors)9 may be
responsible for side-effects, including sedation, hypoten-
sion, weight gain, movement disorders and seizures.1,2
An analysis of the receptor interaction profile of market-
ed antipsychotics10,11 led to the identification of five key
receptors for selective antagonism, D3, D2, 5-HT2A,
The pathophysiology of this complex and uniquely
human disorder is believed to be associated with dopa-
minergic hyperactivity in the mesolimbic system of the
brain.4 Both first generation, typical antipsychotics
(e.g., Haloperidol)2,4,5 and newer atypical antipsychotics
(e.g., Olanzapine and Aripiprazole)6,7 modulate dopa-
minergic hyperactivity either by post-synaptic dopamine
D2 receptor antagonism1 and/or partial agonism8 at pre-
5-HT2C, 5-HT6 (Table 1) that should provide effective
treatment of the disease alongside a reduced side-effect
liability. Thus, dopamine D2/D3 receptor antagonism12
is important for treatment of positive symptoms of
schizophrenia; 5-HT2A receptor antagonism is believed
to contribute to an atypical antipsychotic profile;13
5-HT2C receptor blockade has been reported to counter-
act dopamine D2-mediated extra-pyramidal side-effects
(EPS)14 and may also confer anxiolytic/antidepressant
properties;15 5-HT6 receptor antagonism may address
cognitive deficits.16 Equally important for the identifica-
tion of a superior antipsychotic drug is the exclusion of
Keywords: Dopamine; Serotonin; Antagonist; Sulfonamide; Benzaze-
pine; Atypical; Antipsychotic; Schizophrenia.
*
Corresponding author. Tel.: +44 1279 627488; fax: +44 1279
622790; e-mail: Vincenzo_2_garzya@gsk.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.10.036

V. Garzya et al. / Bioorg. Med. Chem. Lett. 17 (2007) 400–405
401
Table 1. Target profile
ring and the ring size in the right-hand side of molecule
(5). The general synthetic process is highlighted in
Scheme 1: sulfonamides (5) were synthesised by cou-
pling sulfonyl chlorides (2) with the anilines (3) to afford
intermediates (4) that were deprotected to yield tar-
get molecules (5a; R = H); sulfonamides (5b; R =
methyl) were prepared by reductive alkylation of the
basic nitrogen using formaldehyde and sodium
triacetoxyborohydride.18
Receptor
D3
pKi
Beneficial effect from receptor antagonism
>8
Antipsychotic activity (treatment of
positive and negative symptoms)
D2
5-HT2A
7–8a
>8
Contributes to antipsychotic activity and
atypicality
5-HT2C
>8
Counteracts D2-mediated extrapyramidal
side-effect (EPS)
Anxiolytic effect
Antidepressant effect
Addresses cognitive deficits
The first step in our lead optimisation programme aimed
to examine the effect of the benzofused ring size and the
alkylation effect of the basic nitrogen. Thus, three differ-
ent ring systems were explored: the five (isoindoline), the
six (tetrahydroisoquinoline) and the seven (benzazepine)
membered rings as shown in Table 2.
5-HT6
>8
a A slightly lower target affinity at the D2 receptor was chosen in order
to minimize the risk of D2-mediated side-effects that occur at high
levels of receptor occupancy.17
receptor interactions that may lead to unwanted side-ef-
fects and consequently impaired efficacy via reduced
compliance.
Primary receptor binding screening was based upon
inhibition of radioligand binding to recombinant human
dopamine D3, D2, receptors19 and serotonin 5-HT2A, 5-
HT2C and 5-HT6 receptors,20 which provided the pKi
values reported in the tables.
In 2001 we embarked on a research programme at
GlaxoSmithKline to discover novel chemical entities
with the above profile (Table 1). Cross screening identi-
fied molecule (1) in Figure 1, a lead compound with
many of the desired affinities, and with a structure which
was particularly suitable for high-throughput array
chemistry.
An analysis of the three ring systems in (6), (8) and (10)
reported in Table 2 indicates that the benzazepine (10)
possesses the best overall receptor binding profile for
both dopamine and serotonin receptors. Methylation
of the basic nitrogen had a marked beneficial effect for
five- and seven-membered ring systems only: in particu-
lar from compounds (10) to (11), the receptor binding
profile was improved for dopamine D2, D3, and for sero-
tonin 5-HT2A and 5-HT2C with a slight increase in 5-
HT6 affinity. Other substituents on the benzazepine
nitrogen (e.g., ethyl, isopropyl and benzyl) did not bring
dopamine and/or serotonin receptor affinities up to the
desired target levels. Overall, compound (11) was the
The main focus of our SAR study was to bring affinities
of (1) to target levels at our panel of five key receptors
(Table 1) and to identify compounds for further
progression.
Examination of lead molecule (1) led us to focus on
three main areas for structural manipulation: the aryl
substituent (Ar), substitution (X) in the core benzene
pKi: D3 = 8.0
D2 = 6.0
O
O
N
S
H
N
H
5-HT2A = 7.9
5-HT2C = 7.5
5-HT6 = 7.6
(1)
Figure 1. Lead molecule sulfonamide (1).
X
X
X
O
O
(b)
O
O
(a)
O
O
NR
NBoc
S
NBoc
S
S
Ar
Cl
Ar
N
H2N
N
Ar
H
H
(2)
(3)
(4)
(5a): R= H
(c)
(5b): R= CH3
Scheme 1. General synthetic scheme and reaction conditions (a,b)18 for the preparation of sulfonamide type (5). The arrows point out the areas
involved in the SAR exploration.

402
V. Garzya et al. / Bioorg. Med. Chem. Lett. 17 (2007) 400–405
Table 2. Effect of ring size and nitrogen alkylation in the right-hand side of the molecule
O
O
NH/Me
S
N
H
Compound
Ring system
pKia
D3
D2
5-HT2A
5-HT2C
ndb
5-HT6
(6)
7.4 0.08
7.7 0.04
7.9 0.04
7.6 0.04
7.8 0.00
8.7 0.05
6.1 0.13
ndb
7.3 0.05
NH
N
(7)
6.7 0.02
6.1 0.09
6.4 0.06
6.8 0.01
7.5 0.14
8.3 0.03
7.9 0.02
ndb
8.0 0.03
7.5 0.03
ndb
8.3 0.01
7.6 0.1
ndb
CH3
(8)
N
N
H
(9)
CH3
(10)
(11)
7.8 0.03
8.3 0.10
7.3 0.03
8.0 0.07
8.7 0.07
8.9 0.03
NH
N
CH3
a pKi values represent means of at least three determinations for each compound reported in the table.
b Not determined.
best molecule in this series displaying the required target
profile (Table 1) at all five key receptors.
and (18) led to a drop in potency across the whole
set of receptors.
Although possessing the desired in vitro profile, lead
compound (11) showed high blood clearance (81 mL/
min/kg) and major P450 liabilities (see Table 5) pre-
sumably due to metabolism taking place at the
extended alkyl chain. In order to obviate this problem,
the n-butyl group was replaced with a range of aryl
substituents (Table 3) to endeavour to improve PK
properties while maintaining the desired receptor
profile.
Further SAR exploration focussed on substitution at
8-position of the benzazepine aromatic ring to endeav-
our to further improve the in vitro profile of molecule
(12).
The methyl group at the 8-position in (19, Table 4) im-
proved both dopamine and 5-HT2A receptor binding,
but was detrimental for 5-HT2C and 5-HT6 receptor
affinities. Increasing the bulk of the eight-substituent
by the isopropyl group (20) lowered D3 and D2 receptor
affinities, with a slight increase for 5-HT2C receptor.
Bulky halogens at the 8-position in (21) and (22) en-
hanced dopamine D3 profile but were detrimental for
5-HT6 receptor affinity. Interestingly, the chloro ana-
logue (22) was beneficial for 5-HT2A receptor affinity
and had a slightly better overall profile compared to
the bromo analogue (21).
Encouragingly, replacement of the butyl side chain
with the 4-chlorophenyl substituent in (12) retains
many of the desired activities, although the 5-HT2A
receptor affinity is considerably reduced. Compound
(13) has a broadly similar profile. Substitution of the
outer ring with the more polar cyano group in (14) re-
duced affinity at all five receptors. Substitution of the
inner benzene ring with a methyl group, in (15), gave
a slight increase for dopamine D2 and serotonin 5-
HT2C receptors but it did not have any effect on 5-
HT2A. When the inner ring was replaced with a five-
membered ring in (16) changing the geometry of the
molecule, only 5-HT6 receptor binding held up. Het-
erocycles replacing the outer benzene ring in (17)
Of major importance were alkoxy substituted deriva-
tives (23) and (24) which displayed a significant in-
crease in D2, D3 and 5-HT2A receptor affinities.
Unfortunately, the D2 receptor affinity for these two
compounds had extended outside our target range
(Table 1). However, the best overall receptor binding

V. Garzya et al. / Bioorg. Med. Chem. Lett. 17 (2007) 400–405
403
Table 3. Left-hand side modifications
O
O
N
CH3
S
Ar
N
H
Compound
Ar
pKia
D3
D2
5-HT2A
5-HT2C
5-HT6
(11)
8.7 0.05
7.5 0.14
8.3 0.10
7.9 0.07
8.9 0.03
(12)
(13)
7.8 0.15
6.8 0.11
6.7 0.07
7.7 0.03
8.3 0.05
Cl
Cl
8.4 0.07
7.3 0.09
7.3 0.05
7.5 0.04
8.1 0.05
F
(14)
7.8 0.13
6.3 0.10
6.1 0.14
7.0 0.1
7.6 0.04
N
H3C
(15)
(16)
(17)
8.2 0.05
7.4 0.04
7.6 0.07
7.5 002
6.4 0.06
6.5 0.08
6.9 0.04
7.3 0.05
6.9 0.04
7.9 0.09
8.3 0.08
8.4 0.13
8.2 0.05
Cl
S
ndb
Cl
7.3 0.02
S
H3C
H3C
(18)
7.8 0.03
7.0 0.03
5.9 0.03
6.4 0.10
8.0 0.13
O
N
CH3
profile was achieved with the 8-dimethylamino deriva-
tive (25) which possessed excellent affinities at all tar-
geted receptors.
agingly, this molecule showed a moderate blood clear-
ance of 39 mL/min/kg, good oral bioavailability and
half-life (F = 69%, t1/2 = 1.8 h) and good CNS penetra-
tion (brain/blood = 3.4:1).
Table 5 compares the P450 profile of the three main
molecules discussed thus far: replacement of the n-butyl
chain, in (11) with 4-chlorobenzene in (12), contributed
to improve the P450 profile of the target molecule. In
particular, sulfonamide (25) was devoid of major P450
interactions.
The synthesis21,22 of sulfonamide (25) is reported in
Scheme 2. Thus, 8-hydroxybenzazepine (26) was nitrat-
ed and reacted with triflic-chloride to afford triflate
intermediate (28). Buchwald chemistry with dimethyl-
amine followed by catalytic hydrogenation afforded
compound (29). Coupling with the appropriate sulfonyl
chloride and reductive alkylation with formaldehyde
afforded the target material (25).
As compound (25) fulfilled all our in vitro criteria, it was
progressed for further evaluation into DMPK. Encour-

404
V. Garzya et al. / Bioorg. Med. Chem. Lett. 17 (2007) 400–405
Table 4. Eight-position modifications
8
X
O
O
N
CH3
S
N
H
Cl
Compound
X
pKia
D3
D2
5-HT2A
5-HT2C
5-HT6
(12)
(19)
(20)
(21)
(22)
(23)
(24)
(25)
H
Me
8.0 0.15
8.8 0.04
8.4 0.05
8.3 0.12
8.6 0.01
9.1 0.00
9.1 0.03
8.5 0.02
7.0 0.11
7.8 0.04
7.0 0.02
7.2 0.02
7.4 0.01
8.4 0.00
8.2 0.02
7.3 0.04
6.7 0.07
7.7 0.15
8.3 0.11
ndb
7.7 0.03
7.1 0.04
7.8 0.04
6.9 0.07
7.4 0.02
7.4 0.01
7.4 0.01
8.3 0.02
8.3 0.05
7.8 0.04
7.9 0.10
7.3 0.01
7.3 0.02
8.0 0.05
7.5 0.09
8.1 0.05
i-Pr
Br
Cl
7.5 0.06
7.6 0.00
7.8 0.03
8.8 0.06
MeO
i-PrO
NMe2
a pKi values represent means of at least three determinations for each compound reported in the table.
b Not determined.
Table 5. Affinities (IC50, lM) at cytochrome P450 isoforms
X
O
O
N
CH3
S
Ar
N
H
Compound
Ar
X
H
2C19
0.5
2C9
2D6
1.6
3A4
12
3A4
24
1A2
23
(11)
47
45
17
(12)
(25)
H
16
25
1.5
58
40
25
51
Cl
Cl
NMe2
19
7.5
5.7
HO
TfO
HO
(a)
(b)
NBoc
NBoc
O
O
NBoc
N+
N+
O
O
(26)
(27)
(28)
H3C
CH3
N
O
CH3
O
N
CH3
S
N
(c), (d)
(e), (f), (g)
N
H3C
H
NBoc
H2N
Cl
Scheme 2. Synthesis and reaction conditions (a–g)21 for the preparation of target molecule (25).
(29)
(25)

V. Garzya et al. / Bioorg. Med. Chem. Lett. 17 (2007) 400–405
405
2003, 27, 1081; (c) Leriche, L.; Scharz, J.-C.; Sokoloff, P.
Neuropharmacology 2003, 45, 174.
13. (a) Meltzer, H. Y.; Matsubara, S.; Lee, J. C. J. Pharm.
Exp. Ther. 1989, 251, 238; (b) See http://en.sanofi-synthe-
labo.com/Images/44_1124.pdf/.
In our functional assay compound (25) did not show
any agonist activity23 at the five key receptors; sulfon-
amide (25) was, therefore, progressed for evaluation in
our in vivo pharmacodynamic model (reversal of
amphetamine-induced hyperactivity in the rat),24 where
it was shown to be active with an ED50 of 20.6 mg/kg
following oral dosing. Moreover, compound (25) did
not show any propensity to induce catalepsy (a rat mod-
el of dopamine D2-mediated EPS)14 in rats at up to
100 mg/kg p.o.
14. Reavill, C.; Kettle, A.; Holland, V.; Riley, G. J.; Black-
burn, T. P. Br. J. Pharmacol. 1999, 126, 572.
15. Wood, M. D.; Reavill, C.; Trail, B.; Wilson, A.; Stean, T.;
Kennet, G. A.; Lightowler, S.; Blackburn, T. P.; Thomas,
D. R.; Gager, T. L.; Riley, G. J.; Holland, V.; Bromidge,
S. M.; Forbes, I. T.; Middlemiss, D. N. Neuropharmacol-
ogy 2001, 41, 186.
16. Reavill, C.; Rogers, D. C. Curr. Opin. Investig. Drugs
2001, 2, 104.
17. Kapur, S.; Zipursky, R.; Jones, C.; Remington, G.; Houle,
S. Am. J. Psychiatry 2000, 157, 514.
In summary, we have identified a panel of five key recep-
tors whose blockade we believe will deliver a superior
antipsychotic effect. A rational SAR study around the
early lead compound (1) led us to identify the sulfon-
amide (25), a molecule with the desired profile across
dopaminergic and serotoninergic receptors and with a
good DMPK profile. Furthermore, target molecule
(25) showed in vivo activity at 20.6 mg/kg po and no
EPS liability at up to 100 mg/kg po thus providing a
substantial Therapeutic Index.
18. (a) ArSO2Cl, pyr, dichloromethane, room temperature,
12 h, 80%; (b) Ethanolic HCl, EtOH, room temperature,
2 h, 78%; (c) aq CH2O, NaBH(OAc)3, Et3N, 1,2-dichlo-
roethane, room temperature, 12 h, total conversion.
19. Reavill, C.; Taylor, S. G.; Wood, M. D.; Ashmeade, T.;
Austin, N. E.; Avenell, K. Y.; Boyfield, I.; Branch, C. L.;
Cilia, J.; Coldwell, M. C.; Hadley, M. S.; Hunter, A. J.;
Jeffrey, P.; Jewitt, F.; Johnson, C. N.; Jones, D. N.;
Medhurst, A. D.; Middlemiss, D. N.; Nash, D. J.; Riley,
G. J.; Routledge, C.; Stemp, G.; Thewlis, K. M.; Trail, B.;
Vong, A. K.; Hagan, J. J. Pharm. Exp. Ther. 2000, 294,
1154.
Further studies in this area will be the subject of a fur-
ther publication.
20. Wood, M. D.; Scott, C.; Clarke, K.; Cato, K. J.; Patel, N.;
Heath, J.; Worby, A.; Gordon, L.; Campbell, L.; Riley,
G.; Davies, C. H.; Gribble, A. D.; Jones, D. N. C. CNS &
Neurological Disorders – Drug targets 2006, 5, 445.
21. (a) HNO3, dichloromethane, 0–10 °C, 1.5 h, 50%; (b)
TfCl, Et3N, acetone, 0 °C, 30 min, 87%; (c) Me2NH2Cl,
Pd(OAc)2, BINAP, Cs2CO3, dioxan, microwave reactor,
160 °C, 30 min, 70%; (d) H2, Pd–C, 50 psi, EtOH, room
temperature, 6 h, total conversion; (e) ArSO2Cl, pyr,
dichloromethane, room temperature, 12 h, 80%; (f) Eth-
anolic HCl, EtOH, room temperature, 2 h, 78%; (g) aq
CH2O, NaBH(OAc)3, Et3N, 1,2-dichloroethane, room
temperature, 12 h, total conversion.
Acknowledgment
We thank Kevin D. Read, Andrew Reid, Anna Watson,
and Bruce Brown for their valuable contribution.
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