Discovery of benzoylpiperazines as a novel class of potent and selective GlyT1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.07.086

Screening of the Roche compound library led to the identification of the benzoylpiperazine 7 as a structurally novel GlyT1 inhibitor. The SAR which was developed in this series resulted in the discovery of highly potent compounds displaying excellent sele

Full text of DOI:10.1016/j.bmcl.2008.07.086

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5134–5139
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of benzoylpiperazines as a novel class of potent and selective
GlyT1 inhibitors
b
b
a
c
a
Emmanuel Pinard a, , Daniela Alberati , Edilio Borroni , Holger Fischer , Dominik Hainzl , Synèse Jolidon ,
Jean-Luc Moreau b, Robert Narquizian a, Matthias Nettekoven a, Roger D. Norcross a, Henri Stalder a,
Andrew W. Thomas a
*
a F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland
b F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, CNS Disease Biology Area, CH-4070 Basel, Switzerland
c F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Non Clinical Safety, CH-4070 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Screening of the Roche compound library led to the identification of the benzoylpiperazine 7 as a struc-
turally novel GlyT1 inhibitor. The SAR which was developed in this series resulted in the discovery of
highly potent compounds displaying excellent selectivity against the GlyT2 isoform, drug-like properties,
and in vivo efficacy after oral administration.
Received 4 July 2008
Revised 18 July 2008
Accepted 19 July 2008
Available online 24 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
GlyT1
Glycine
Transporter
Inhibitor
Schizophrenia
NMDA
Benzoylpiperazine
Both clinical observations and preclinical studies suggest that
hypofunction of N-methyl- -aspartate (NMDA) receptor is impli-
cently on the optimization of the non-sarcosine based spiropiperi-
dine 6.11
D
cated in the pathophysiology of schizophrenia.1 Thus, therapeutic
intervention aiming at restoring NMDA receptor activity repre-
sents a promising novel strategy for the management of schizo-
phrenia. As glycine is an obligatory co-agonist at the NMDA
receptor complex,2 one strategy to enhance NMDA receptor activ-
ity is to elevate extracellular levels of glycine in the brain through
selective inhibition of glycine uptake mediated by the glycine
transporter-1 (GlyT1), which is co-expressed with the NMDA
receptor.3 Strong support for this approach comes from clinical
During our continued efforts to discover and develop structur-
ally novel and selective GlyT1 inhibitors, the Roche compound col-
lection was screened. This campaign led to the identification of the
benzoylpiperazine hit 7 as a potent inhibitor of GlyT1 (15 nM),
showing more than 300-fold selectivity against the type 2 isoform.
7 is characterized by the presence on the benzoyl moiety of a mor-
pholine and
respectively.
a nitro group occupying positions 2 and 5,
In this letter, we describe the SAR studies obtained in this novel
benzoylpiperazine class at positions 2, 5, and at the left-hand aro-
matic ring attached to the piperazine moiety (Fig. 2). We also re-
port on the strategy we followed that led to the identification of
highly potent and selective analogues displaying drug-like proper-
ties and in vivo efficacy after oral administration.
studies where glycine and D-serine (co-agonists at the glycine site
of NMDA receptor) and sarcosine (a prototypical weak GlyT1 inhib-
itor) improved positive, negative, and cognitive symptoms in
schizophrenic patients, when added to conventional therapy.4 As
a result, considerable efforts have been focused on the develop-
ment of selective GlyT1 inhibitors.5 The first examples reported
were sarcosine derivatives including 1,6 2,7 and 3.8 More recently,
non-amino-acid chemotypes like 49 and 5,10 have been described
(Fig. 1). We have also contributed to this field and reported re-
Our synthetic strategy12 entailed mainly two straightforward
and complementary approaches allowing for rapid modification
of the three exit vectors around the central benzoylpiperazine core
(Scheme 1). The first route that led to the amino analogues 13, 15–
18, and 20–26 involved the reaction under thermal conditions of
amines with the 2-halogen-substituted benzoyl piperazine precur-
sors 67a–d prepared under standard amide coupling conditions
* Corresponding author. Tel.: +41 61 688 43 88; fax: +41 61 688 87 14.
E-mail address: emmanuel.pinard@roche.com (E. Pinard).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.07.086

E. Pinard et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5134–5139
5135
O
OH
N
N
O
N
O
S
O
OH
N
O
OH
Cl
O
F
3: Lu AA20465
2: Org-25935
1: ALX-5407
H
O
N
Cl
O
O
O
N
N
N
N
H
H
HN
O
N
O
Cl
N
S
O
Cl
F
F
F
6
4: SSR504734
5
O
O
N
2
F
N
N
5
NO2
O
7
Figure 1. GlyT1 inhibitors.
give (8) resulted in the complete loss of GlyT1 activity. Similar det-
rimental effect was observed after its replacement with either elec-
tron-donating or neutral groups (9–10) as well as with lipophilic
electron-withdrawing (EWG) groups (11–12).
O
2
N
N
5
In contrast, in vitro potency recovered with the introduction of
polar EWG groups (13–16). In particular, high activity was ob-
tained with the methylsulfone (14), methylsulfonamide (15), and
sulfonamide (16) derivatives, respectively, showing 70, 100, and
120 nM activity at GlyT1. Gratifyingly, the introduction of such
groups simultaneously abolished the low micromolar activity at
the GlyT2 isoform seen with the starting hit 7. Introduction of lar-
ger substituents than methyl on the sulfonyl group (17–18) re-
sulted in a severe drop in GlyT1 activity, which we postulate to
be due to limited space available in this region of the receptor.
Molecular properties as well as metabolic stability in rat and
human liver microsomes for the most active nitro (7), nitrile
(13), methylsulfone (14), and sulfonamides (15–16) analogues
were measured (Table 2). All these derivatives possessed excellent
membrane permeability as measured in the Pampa assay16 and
furthermore, the sulfone and sulfonamide derivatives (14–16)
exhibited a much higher aqueous solubility (pH 6.5) compared to
the nitro and nitrile analogues 7 and 13. As expected, the two sul-
fonamides displayed the highest polar surface area (PSA) above
90 Å2, raising concern regarding the ability of these two com-
pounds to penetrate the central nervous system (CNS). Lower
Figure 2. Core benzoylpiperazine structure and the three exit vectors explored.
from the 2-halogen-benzoic acids 68a–d and piperazine 69. The
second route that led to compounds 7, 8, 10–12, 14, 19, and 27–
66 consisted in coupling the aryl piperazine 70 with the appropri-
ately functionalized benzoic acids 71a–d. Well-established meth-
ods were used for the preparation of these acids from their
precursors 72a–d as indicated in Scheme 1: Mitsunobu alkylation
for the 2-alkoxy-substituted acid 71a, thermal conditions for the
2-alkylsulfanyl and 2-alkylamino-substituted acids 71b–c, and Su-
zuki coupling for the 2-aryl- or 2-cycloalkyl-substituted acids
71d.13
Starting from 7, our first effort was aimed at identifying suitable
groups in position 5 of the benzoyl ring to replace the nitro substi-
tuent: a moiety often causing safety concerns due to its well-doc-
umented mutagenic and carcinogenic potential.15 Table
1
summarizes the in vitro potency at GlyT1 and selectivity against
GlyT2 of analogues prepared. First, removal of the nitro group to

5136
E. Pinard et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5134–5139
F
NH
O
N
N
R
R`
O
X
O
O
N
RR`N: morpholinyl
R1: NO2
O
X
F
N
F
N
F
N
69
O
N
HO
N
N
R1
R1
NH2
R1
(a)
(c)
(b)
O
O
O
a: R1: NO2; X: F
b: R1: CN; X: Br
9
13, 15-18, 20-26
68a-d
67a-d
c: R1: SO2NHR; X: Cl
d: R1: SO2R; X: Cl
O
OH
O
F
HO
HO
O
S O
O
S O
72a
72b
(d-e)
(b) or (f)
O
F
HO
NH
O
R2
R1
N
O
R2
R3
R1
N
70
HO
(g)
N
R3
72c
R1
(a)
O
I
7, 8,10-12,14, 19, 27-66
71a-d
a: R1: SO2Me; R2: OR
b: R1: SO2Me; R2: NRR`or SR
HO
(h) or (i-j)
O
S O
c: R1: H or Me or Br or CF3; R2: NRR`
d: R1: SO2Me; R2: Ar or c-C6H11
72d
Scheme 1. Synthesis of benzoylpiperazines 7–66. Reagents and conditions: (a) TBTU, DIPEA, DMF, rt, 60–95%; (b) RR0NH, THF, 80 °C, 70–97%; (c) H2 (1 atm), Pd/C, MeOH, rt,
80%; (d) MeOH, cat. H2SO4, reflux, 90%; (e) ROH, di-tert-butyl-azodicarboxylate, triphenylphosphine, THF, rt then NaOH, 50 °C, 95–100%; (f) RSH, Cs2CO3, DMA, 90 °C, 88%; (g)
RR0NH, dioxane, sealed tube, 130 °C, 67–92%; (h) ArB(OH)2, cat. Pd(OAc)2, Na2CO3, H2O, rt, 92–95%; (i) 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, cat.
Pd(dppf)Cl2, KOH, dioxane, 80 °C, 57%; (j) Pd/C, ammonium formate, MeOH, reflux, 80%.
Table 1
Table 2
In vitro inhibitory activity of 7–18 at GlyT1 and GlyT2a
Molecular properties and microsomal clearances for 7, 13–16
O
N
Compound Pampa, Solubilityb PSAc CLintd (rat
CLintd (human
microsomes)
Pea
microsomes)
7
4.7
6.1
3.1
5.3
3.3
9
92
73
82
94
105
106
53
40
106
nd
35
31
26
43
31
O
13
14
15
16
<1
30
30
308
F
N
N
R1
Pe: permeation constant (10ꢀ6 cm/s).16
a
Solubility (
l
g/mL) measured in a lyophilization solubility assay.17
b
c
O
PSA: polar surface area calculated with Moloc.18
d
CLint: intrinsic clearance (lL/min/mg protein).
b
b
Compound
R1
GlyT1 EC50
(
lM)
GlyT2 EC50 (lM)
Selectivityc
320
7
8
9
NO2
H
NH2
CH3
Br
CF3
CN
SO2Me
SO2NHMe
SO2NH2
SO2n-Pr
SO2CH2Ph
0.015
>30
>30
>30
>30
26.0
0.18
0.07
0.1
4.8
nd
and more favorable PSA values were obtained for the nitrile (13)
and the methylsulfone (14) derivatives. Finally, encouraging
microsomal stability data were obtained for the methylsulfone
analogue 14 showing a medium in vitro clearance in both the rat
and human species. Altogether, these results demonstrate that
among the groups tested at position 5, the methylsulfone function
offers the best opportunity to generate compounds having CNS
drug-like properties, and as a result constitutes our preferred motif
at this position. Pleasingly, in a CEREP selectivity screen performed
against a panel of 80 targets including transmembrane and soluble
receptors, enzymes, ion channels, and monoamine transporters,19
the methylsulfone compound 14 exhibited a highly selective pro-
>30
>30
5.1
11.0
13
>30
>30
>30
>30
>30
10
11
12
13
14
15
16
17
18
<0.2
0.4
72
>417
>300
>250
0.12
1.6
>30
a
EC50 values are the average of at least two independent experiments.
[3H]-glycine uptake inhibition assay in cells transfected with hGlyT114a or
b
hGlyT214b cDNAs.
c
Ratio of the EC50 (lM) values GlyT2/GlyT1.
file (< 20% inhibition at 10 lM was measured for all targets).

E. Pinard et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5134–5139
5137
Table 4
Next, SAR exploration at position 2 of the benzoyl ring in hit 7
In vitro inhibitory activity of 33–53 at GlyT1 and GlyT2a
and compound 14 was conducted (Table 3). Deletion of the mor-
pholine unit (19) as well as its replacement with smaller alkyl-
substituted amino groups (20–22) resulted in inactive or weakly
active analogues. Pleasingly, a dramatic improvement in activity
was seen by increasing the size of the alkylamino substituent as
seen with the isopropyl (23), cyclohexyl (24), and piperidinyl
(25) derivatives, which were found to display 1–2 nM activity at
GlyT1. An abrupt drop of activity was, however, observed upon
introduction of more extended substituents like the cyclohexylm-
ethyl group (26), suggesting that substituents at position 2 fit in a
size limited pocket of the GlyT1 receptor. Further SAR exploration
revealed to our delight that activity was in fact not restricted to the
presence of an alkylamino residue at this position and that, on the
contrary, great latitude for variation was possible. Indeed, low
nanomolar GlyT1 activity was also obtained with analogues carry-
ing a wide array of structurally diverse substituents like alkoxy
groups (27-29), alkylsulfanyl groups (30), and aromatic groups
(31–32). All these derivatives, in addition, displayed excellent
selectivity versus the GlyT2 isoform.
Finally, SAR around the left-hand aromatic system was explored
(Table 4). A rapid scanning of electron-donating (–OMe), electron
neutral (–Me), and EWG groups (–Cl and –CF3) at the ortho, meta,
and para positions of the aromatic ring (33–44) revealed that best
activity was reached with the presence of an EWG group in para
position, as exemplified with the 4-trifluoromethyl-substituted
derivative 44: 100 nM. In fact, further exploration showed that a
variety of EWGs were allowed at this position. Indeed, not only
lipophilic groups, but also moderately or strongly polar substitu-
ents were tolerated such as the cyano (45) or the methylsulfone
group (46). Keeping these preferred motifs in place, a significant
improvement in GlyT1 potency was measured upon the introduc-
tion of an additional EWG like fluorine, or cyano group at either the
ortho or meta position as observed with compounds 47–51. Inter-
estingly, the replacement of the aromatic nucleus with heteroaro-
matic systems as exemplified with pyridine derivatives 52 and 53
O
O
N
N
N
R3
NO2
b
b
Compound
R3
GlyT1 EC50
(lM)
GlyT2 EC50 (lM)
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
2-OMe-Ph
2-Me-Ph
2-Cl-Ph
2-CF3-Ph
3-OMe-Ph
3-Me-Ph
3-Cl-Ph
3-CF3-Ph
4-OMe-Ph
4-Me-Ph
4-Cl-Ph
>10
>10
1.4
7.1
0.53
1.1
0.7
0.4
1.3
13.4
14.2
11.2
>30
8.3
4.0
3.1
0.3
11.4
7.7
1.17
3.3
1.1
2.1
4.3
>30
>30
29
15
24
2.9
0.31
0.1
4-CF3-Ph
4-CN-Ph
4-SO2Me
0.078
0.11
0.03
0.04
0.015
0.041
0.037
0.033
0.047
2-F, 4-CN-Ph
2-F, 4-SO2Me
2-CN, 4-CF3-Ph
2-F, 4-CF3-Ph
3-F, 4-CF3-Ph
5-CF3, 6-Cl-2-Py
3-Cl, 5-CF3-2-Py
>30
a
EC50 values are the average of at least two independent experiments.
[3H]-glycine uptake inhibition assay in cells transfected with hGlyT114a or
b
hGlyT214b cDNAs.
was well tolerated. With all active derivatives, good to excellent
selectivity against the GlyT2 isoform was seen (Table 4).
Having established a preliminary SAR at the three exit vectors
around the central benzoylpiperazine core, the next step consisted
in combining some of the preferred groups identified at the left-
hand side as well as at position 2 on the right-hand benzoyl moi-
ety, while keeping position 5 occupied with the favored methyl-
Table 3
In vitro inhibitory activity of 19–32 at GlyT1 and GlyT2a
O
R2
sulfone group. This approach led to the identification of
a
number of highly potent GlyT1 inhibitors (Table 5), displaying no
activity at the GlyT2 isoform (data not shown). Gratifyingly, the
great structural diversity seen previously at position 2 was also ob-
served with compounds 54–60 incorporating the 4-CF3-phenyl
group at the left-hand side. Indeed, low nanomolar activity was ob-
tained with the alkylamino (54–55), the alkoxy (56–57), the aro-
matic (58–59), and the cycloalkyl (60) derivatives. In view of
their favorable pharmacological activities in vitro, these com-
pounds were assessed for solubility and metabolic stability. Inter-
estingly, as seen in Table 5, the isopropyloxy and
cyclopropylmethylenoxy derivatives 56 and 57 exhibited good
aqueous solubility (pH 6.5) and excellent metabolic stability in
mouse and human liver microsomes. Much less favorable results
were obtained with the corresponding alkylamino, aromatic, and
cycloalkyl compounds (54–55, 58–60), which exhibited, in general,
low solubility and medium microsomal clearance, a result likely
due to the higher lipophilicity of these analogues compared to
the alkoxy derivatives (see clogP, Table 5). Moreover, the positive
influence of alkoxy groups on physico-chemical and metabolic
properties was also observed when more polar left-hand aromatic
rings than the 4-CF3-phenyl group were in place. Indeed, for exam-
ple, the cyclopropylmethylenoxy derivatives 62 and 65 incorporat-
ing, respectively, the cyano and methylsulfone-substituted
F
N
N
R1
O
b
b
Compound
R1
R2
GlyT1 EC50
(
l
M)
GlyT2 EC50 (lM)
19
20
21
22
23
24
25
26
27
28
29
30
31
32
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
H
NH2
NHMe
NMe2
NH-i-Pr
32
>10
1.9
0.5
24.5
3.3
1.4
2.0
10
8.5
4.0
0.002
0.002
0.001
>10
0.039
0.009
0.015
0.015
0.069
0.016
NH-c-C6H11
Piperidin-yl
NH-CH2-c-C6H11
O-i-Pr
nd
>30
>30
>30
>30
>30
>30
O-i-Bu
O-CH2-c-Pr
S-i-Pr
Ph
3-F-Ph
a
EC50 values are the average of at least two independent experiments.
[3H]-glycine uptake inhibition assay in cells transfected with hGlyT114a or
b
hGlyT214b cDNAs.

5138
E. Pinard et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5134–5139
Table 5
In vitro inhibitory activity at GlyT1, molecular properties, and microsomal clearances of 54–66
O
N
R2
N
R3
O S O
a,b
Compound
R3
R2
GlyT1 EC50
(
lM)
clogP
Solubilityc
(lg/mL)
CLintd (mouse microsomes)
CLintd (human microsomes)
54
55
56
57
58
59
60
61
62
63
64
65
66
4-CF3-Ph
4-CF3-Ph
4-CF3-Ph
4-CF3-Ph
4-CF3-Ph
4-CF3-Ph
4-CF3-Ph
2-F, 4-CN-Ph
2-F, 4-CN-Ph
2-F, 4-CN-Ph
2-F, 4-SO2Me
2-F, 4-SO2Me
2-F, 4-SO2Me
Morpholinyl
Piperidin-yl
O-i-Pr
O-CH2-c-Pr
Ph
0.045
0.075
0.082
0.04
0.031
0.029
0.025
0.012
0.016
0.02
1.97
3.5
2.8
3
15
125
0
1
9
10
12
0
<1
62
15
<1
<1
<1
14
31
<1
5
2.97
3.79
3.95
4.52
2.36
1.83
2.64
1.35
0.82
1.62
6
12
12
10
16
4
5
29
1
4-F-Ph
5
-c-C6H11
Piperidin-yl
O-CH2-c-Pr
Ph
Piperidin-yl
O-CH2-c-Pr
Ph
11
33
9
124
53
14
90
0.046
0.052
0.057
50
18
0
a
EC50 values are the average of at least two independent experiments.
[3H]-glycine uptake inhibition assay in cells transfected with hGlyT1.14a
b
c
Solubility (
l
g/mL) measured in a lyophilization solubility assay.17
CLint: intrinsic clearance ( L/min/mg protein).
d
l
aromatic rings consistently exhibited higher solubility and meta-
bolic stability than the corresponding piperidinyl and phenyl ana-
logues 61, 64 and 63, 66.
Among the compounds prepared at this stage, the cyclo-
propylmethylenoxy analogue 62 attracted our most attention since
it demonstrated particularly good in vitro potency at GlyT1
(16 nM), no activity at the GlyT2 isoform up to the highest concen-
250
200
150
100
50
Saline
Compound 62
tration tested (30
lipophilicity: clogP = 1.83, good aqueous solubility: 31
l
M), good physical properties with moderate
g/mL (pH
l
6.5), high membrane permeability: Pe (Pampa): 3.2, and good
mouse and human microsomal stability.
Mean SEM (N=6)
-40 -20 20
0
40
60
80
100
120 140
Consequently, 62 was selected for further evaluation. An in vivo
pharmacokinetic study in mouse (Table 6) revealed that 62, as ex-
pected based on its in vitro profile, exhibited low clearance, good
plasma exposure, excellent oral bioavailability, and moderate plas-
ma protein binding (PPB). Despite demonstrating a relatively low
brain/plasma ratio, 62 could achieve nevertheless a robust expo-
sure in the brain, with a Cmax of 373 ng/g at the dose of 10 mg/kg
(po), above its inhibitory activity at the GlyT1 transporter.
These favorable data prompted us to evaluate the effect of com-
pound 62 on the extracellular level of glycine in mouse striatum
(Fig. 3). We were delighted to observe that 62 produced at the dose
of 10 mg/kg administrated orally, a robust and sustained increase
of glycine levels: 2.3-fold over basal level at 40 min and 1.7-fold
Time (minutes)
Figure 3. Effect of 62 on the extracellular glycine levels in mouse striatum at
10 mg/kg po.
at 140 min. Encouraged by this result, further in vitro profiling in
safety assays was performed.
Compound 62 (like all compounds tested in this series) exhib-
ited no significant inhibition of the major drug metabolizing
CYP450 enzymes (3A4, 2D6, 2C9, 2C19, 1A2; IC50 > 29.1
ever, 62 was found to exhibit a fairly high activity at the hERG
lM). How-
potassium channel with an IC50 of 0.6
clamp assay.20
lM measured in a patch-
In summary, we report here on the discovery of benzoylpipera-
zines as a novel chemotype of GlyT1 inhibitors. Starting from the
chemically tractable HTS hit 7, rapid exploration of SAR accompa-
nied by the early assessment of molecular property and metabolic
stability of the synthesized derivatives allowed the prompt identi-
fication of a highly promising sub-series in which the nitro and
morpholine residues in 7 are replaced, respectively, by a methyl-
sulfone and an alkoxy group. Within this ‘alkoxy-methylsulfone-
benzoylpiperazine’ sub-series, highly potent and selective GlyT1
inhibitors were identified, which as seen with representative com-
pound 62 demonstrated drug-like properties and in vivo efficacy
after oral administration. Results from our subsequent lead optimi-
zation work in this sub-series, which was mainly focused on the
improvement of brain penetration/in vivo activity as well as of
hERG selectivity, will be reported in due course.
Table 6
Pharmacokinetics properties of 62 in mouse
Parameter
Valuea
Iv dose (2 mg/kg)
CL (mL/min/kg)
Vss (L/kg)
9.5
2.8
Po dose (10 mg/kg)
Bioavailability F (%)
T1/2 (h)
Cmax plasma (ng/mL)
Cmax brain (ng/g)
B/P
100
5.8
3875
373
0.1
PPB (% unbound)
12
a
Values are the average of two independent experiments.

E. Pinard et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5134–5139
5139
Zimmerli, D. Bioorg. Med. Chem. Lett. 2006, 16, 4305; (d) Alberati, D.; Hainzl, D.;
Jolidon, S.; Krafft, E. A.; Kurt, A.; Maier, A.; Pinard, E.; Thomas, A. W.; Zimmerli,
D. Bioorg. Med. Chem. Lett. 2006, 16, 4311; (e) Alberati, D.; Hainzl, D.; Jolidon, S.;
Kurt, A.; Pinard, E.; Thomas, A. W.; Zimmerli, D. Bioorg. Med. Chem. Lett. 2006,
16, 4321; (f) Pinard, E.; Alberati, D.; Borroni, E.; Ceccarelli, S. M.; Fischer, H.;
Hainzl, D.; Jolidon, S.; Moreau, J. L.; Stalder, H.; Thomas, A. W. Abstracts of
Papers, 231st ACS National Meeting, Atlanta, GA, United States, March 26–30,
2006; MEDI-407.
Acknowledgments
We thank Markus Bender, Patrick Bourdeaux, Serge Burner,
Virginie Brom, Remy Halm, Hans-Peter Marty, Silvia Meyer, Thierry
Meyer, Bernd Puellmann, Philipp Schmid, Sebastien Schmitt, and
Roger Wermuth for their dedicated technical assistance.
12. Nettekoven, M.; Thomas, A. W. Curr. Med. Chem. 2002, 9, 2179.
13. All intermediates and final compounds were characterized by 1H NMR
(300 MHz) and mass spectroscopy. The following data were obtained for
compounds 56, 57, and 62. Compound 56: 1H NMR (CDCl3): 1.31 (m, 6H), 3.06
(s, 3H), 3.21 (m, 2H), 3.36 (m, 4H), 3.96 (m, 2H), 4.71 (septuplet, J = 6.0, 1H),
6.94 (d, J = 8.6, 2H), 7.04 (d, J = 8.8, 1H), 7.48 (d, J = 8.6, 2H), 7.86 (d, J = 2.3, 1H),
7.93 (dd, J = 2.3, J = 8.8, 1H); MS: m/z (%): 471.2 (100%, M+H+). Compound 57:
1H NMR (CDCl3): 0.34 (m, 2H), 0.62 (m, 2H), 1.26 (m, 1H), 3.06 (s, 3H), 3.22–
3.55 (m, 6H), 3.85–4.12 (m, 4H), 6.94 (d, J = 8.7, 2H), 7.03 (d, J = 8.7, 1H), 7.51
(d, J = 8.7, 2H), 7.88 (d, J = 2.1, 1H), 7.94 (dd, J = 2.1, J = 8.7, 1H); MS: m/z (%):
483.5 (100%, M+H+). Compound 62: 1H NMR (CDCl3): 0.36 (m, 2H), 0.65 (m,
2H), 1.26 (m, 1H), 3.06 (s, 3H), 3.07–3.55 (m, 6H), 3.85–4.05 (m, 4H), 6.92 (t,
J = 8.5, 1H), 7.02 (d, J = 8.7, 1H), 7.31 (dd, J = 1.9, J = 12.4, 1H), 7.39 (d, J = 8.3,
1H), 7.88 (d, J = 2.3, 1H), 7.94 (dd, J = 2.3, J = 8.7, 1H); MS: m/z (%): 458.5 (100%,
M+H+).
14. (a) Ceccarelli, S. M.; Pinard, E.; Stalder, H.; WO Patent 2005040166, 2005;
Chem. Abstr. 2005, 142, 447121; Compound 6 used as positive comparator
displayed an EC50 of 26 nM.; (b) Same conditions as described for the hGlyT1
assay (see Ref. 14a) with slight modifications: conc. [3H]-glycine: 200 nM, cold
glycine not present.
15. For a review, see Purohit, V.; Basu, A. K. Chem. Res. Toxicol. 2000, 13, 673.
16. Kansy, M.; Senner, F.; Gubernator, K. J. Med. Chem. 1998, 41, 1007.
17. Compound initially in DMSO solution is lyophilized, then dissolved in 0.05 M
phosphate buffer (pH 6.5), stirred for 1 h, and shaken for 2 h. After one night,
the solution is filtered and the filtrate is analyzed by direct UV measurement or
by HPLC-UV.
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