Sarcosine based indandione hGlyT1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2005.11.041

A series of sarcosine based indandione hGlyT1 inhibitors has been developed. Optimization of substitution around the indandione and sarcosine moieties has led to highly potent inhibitors at hGlyT1, which show selectivity over a number of other receptors.

Full text of DOI:10.1016/j.bmcl.2005.11.041

Bioorganic & Medicinal Chemistry Letters 16 (2006) 1388–1391
Sarcosine based indandione hGlyT1 inhibitors
Christopher G. Thomson,a,* Karen Duncan,a,b Stephen R. Fletcher,a Ian T. Huscroft,a
Gopalan Pillai,b Piotr Raubo,a Alison J. Smithb and Darren Steada,b
aDepartment of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre,
Terlings Park, Harlow, Essex CM20 2QR, UK
bDepartment of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories,
The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
Received 7 November 2005; revised 10 November 2005; accepted 10 November 2005
Available online 29 November 2005
Abstract—A series of sarcosine based indandione hGlyT1 inhibitors has been developed. Optimization of substitution around
the indandione and sarcosine moieties has led to highly potent inhibitors at hGlyT1, which show selectivity over a number of
other receptors.
Ó 2005 Elsevier Ltd. All rights reserved.
Hypoactivity of NMDA receptor mediated glutamater-
gic neurotransmission has been implicated in induction
of negative symptoms of schizophrenia.1 This is sup-
ported by the fact that competitive NMDA antagonists
elicit psychotomimetic effects in humans.2 As glycine is
necessary as a co-agonist of glutamate at the NMDA
receptor,3 elevating synaptic levels of glycine by inhibi-
tion of the glycine reuptake system should lead to en-
hanced NMDA receptor function. Indeed, inhibitors
of the GlyT1 glycine transporter4 such as NFPS5 and
Org 245986 (Fig. 1) have been shown to elevate glycine
levels in the CNS and reverse PCP-induced behaviour,7
suggesting such compounds may have a role in treating
the negative symptoms of schizophrenia.
2-phenylindan-1,3-dione and sarcosine moieties. The
indandione (1) was readily alkylated with a dibromoal-
kane (Scheme 1) or allyl bromide (Scheme 2; 4,5,6,
X = H). Sarcosine tert-butyl ester was then appended
by nucleophilic displacement or by reductive amination
of the aldehyde formed by ozonolysis of the allyl adduct.
Acid cleavage of the tert-butyl ester gave the amino acid
salt of the desired compound (2).
Synthesis of substituted indandiones (5 and 7) started
from commercially available substituted 1,2-diacids (3)
or anhydrides (4). 3,4-Dichloro-5-methoxy phthalic
acid10 was readily available by oxidation of 2-propyl-
5-methoxy-5,6-dichloroindanone.12 Reaction of the
anhydrides (4) with either phenyl or 4-fluorophenyl ace-
tic acid in acetic anhydride, followed by sodium hydrox-
ide as previously reported,10 gave poor results. This
could be improved to afford an almost quantitative
yield, by replacing aqueous sodium hydroxide with sodi-
um methoxide in methanol, as reported by He et al.11
In-house screening and pharmacophores developed
from published hGlyT1 inhibitors5,6,8 suggested that
indandione-type molecules bearing a pendant sarcosine
moiety might lead to a new series of hGlyT1 antago-
nists. The chemistry and structure–activity relationships
(SARs) of this new series are described in this
communication.
Initial chemistry efforts focussed on discovering the
optimum chain length between commercially available
Keywords: Sarcosine; Indandione; GlyT1 inhibitors; Selectivity;
Potent.
*
Corresponding author. Tel.: +441279440563; e-mail: christopher_
thomson@merck.com
Figure 1. Sarcosine containing GlyT1 inhibitors.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.11.041

C. G. Thomson et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1388–1391
1389
Scheme 1. Reagents and conditions: (i) 1,3-dibromopropane or 1,4-
dibromobutane, K2CO3, acetone, 24 h, 60 °C, 80–95% yield; (ii)
sarcosine tert-butyl ester hydrochloride, K2CO3, acetone, 72 h,
60 °C, 80% yield; (iii) TFA, DCM, 18 h, rt, 70–75% yield.
Scheme 3. Reagents and conditions: (i) amino acid tert-butyl ester,
NaBH(OAc)3, DCM, rt, 18 h, 50–80% yield; (ii) HCHO, NaBH3CN,
MeCN, rt, 18 h, 40–85% yield; (iii) TFA, DCM, 18 h, rt, 70–75% yield.
Table 1.
Compound
n
hGlyT1a IC50 (nM)
2a
2b
2c
3
2
1
13% at 3 lM
2800
103
Values represent geometric means of 3–6 determinations.
a Functional assay measuring inhibition of uptake of [14C]glycine into
human JAR cells expressing hGlyT1a.9
Table 2.
Scheme 2. Reagents and conditions: (i) Ac2O, 1 h, reflux, 90% yield;
(ii) 4-fluorophenyl or phenylacetic acid, Ac2O, Et3N, reflux, 1.5 h, then
NaOMe, MeOH, reflux, 0.75 h, 90–98% yield; (iii) allyl bromide,
K2CO3, acetone, 18 h, rt, quantitative; (iv) O3, MeOH, DCM, À78 °C,
0.5 h, DMS, rt, 18 h, 80% yield; (v) amino acid tert-butyl ester,
NaBH(OAc)3, DCM, rt, 18 h, 90% yield; (vi) TFA, DCM, 18 h, rt,
70–75% yield.
Compound
4
5
6
hGlyT1a IC50 (nM)
2c
5a
5b
5c
5d
H
F
H
H
103
85
Aldehyde 6 was formed by allylation and ozonolysis as
previously described. Substituted sarcosine derivatives
were formed by reductive amination of 6 with the rele-
vant amino acid tert-butyl ester. Where the substituted
N-methyl amino acid fragment was not available, the
primary amino acid ester was used, followed by reduc-
tive methylation with formaldehyde (Scheme 3).
H
H
H
H
Cl
Cl
Cl
Cl
H
Cl
28
19
OMe
1.9
Values represent geometric means of 3–6 determinations.
a Functional assay measuring inhibition of uptake of [14C]glycine into
human JAR cells expressing hGlyT1a.9
In the case of compound 7d, only the methyl ester of iso-
butyric acid was available, so final hydrolysis was via
1 M sulfuric acid in 1,4-dioxane at elevated temperature.
Compound 7f was formed using O-t-butyl-protected ser-
ine t-butyl ester; hence, a final treatment with trifluoro-
acetic acid unmasked both acid and hydroxyl group.
The initially unsubstituted compounds 2a–c (Table 1)
showed that a two carbon linker between the indandione
and sarcosine was optimal for hGlyT1 potency. Substi-
tution around compound 2c was then explored (Table
2), showing that 4,5-dichloro-6-methoxy substitution

1390
C. G. Thomson et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1388–1391
14
(>1000-fold selective) to hGlyT2,9 h5HT1A
,
Table 3.
15
16
h5HT2A
,
hD2 and hERG17 making them selective
tools for elucidating further the effects of hGlyT1
inhibition.
A novel series of sarcosine based indandione hGlyT1
inhibitors has been investigated. With suitable substitu-
tion around the indandione and on the amino acid, po-
tent inhibitors have been discovered, with selectivity
over a number of receptors. The SAR around the amino
acid is extremely sensitive, showing stereochemical pref-
erence with small groups, leading to compound 7c, with
excellent potency at hGlyT1.
Compound
X
H
NR1R2
hGlyT1a IC50 (nM)
1.9
5d
7a
7b
7c
7d
7e
7f
F
H
H
F
F
F
0.95
Acknowledgments
19
The authors thank Cristina Cuadrillero, Consuelo
´
´
Tudela and Ana Marıa Teran at Merck Sharp &
Dohme, CIBE (Spain) for counterscreening results.
0.47
38% at 3 lM
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