5536
S. Jolidon et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5533–5536
Table 4
1 containing a benzodiazepinone moiety we sequentially modified
the original molecule to get structurally simple and potent bis-
amides of the type 2 showing excellent metabolic stabilities. Fur-
ther optimization of this new class of GlyT1 inhibitors will be re-
ported in due course.
In vitro inhibitory activity of the two enantiomers of 37 at GlyT1 and GlyT2a
Cl
O
H
37
N
N
Acknowledgments
*
H
O
Cl
We thank Markus Bender, Serge Burner, Virginie Brom, Remy
Halm, Hans-Peter Marty, Thierry Meyer, Philipp Schmid, Daniel
Zimmerli, Judith Lengyel and Nicole Hauser for their dedicated
technical assistance.
Specific rotationb
GlyT1 EC50
(lM)
GlyT2 EC50 (lM)
c
c
Compounds
37 (+)
37 (À)
+ 17.6°
À19.4°
0.30
0.28
28
5.9
a
EC50 values are the average of at least two independent experiments.
b
c
References and notes
Measured in MeOH (c = 1; 589 nm, 20°).
[3H]-glycine uptake inhibition assay in cells transfected with hGlyT119a or
hGlyT219bcDNAs.
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Table 5
Molecular properties and microsomal clearances of representative derivatives of the
bis-amides 2
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Ar1
O
H
R1
N
Ar2
N
H
O
24
25
13
8
Membrane permeabilitya[.10À6
High
Pe = 2.0
<1
n.d.
9.7
Medium
Pe = 1.0
<1
High
Pe = 2.2
7
n.d.
cm/s]
Solubilityb
(
l
g/ml)
<1
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19. (a) Ceccarelli, S. M.; Pinard, E.; Stalder, H. WO Patent 2005040166, 2005; Chem.
Abstr. 2005, 142, 447121.; (b) Same conditions as described for the hGlyT1
assay (see Ref. 11a) with slight modifications: conc. [3H]-glycine: 200 nM, cold
glycine not present.
c
Clint (Mouse microsomes)
19.3
0
8.6
0
926
887
c
Clint (Human microsomes)
Membrane permeability is measured in the PAMPA assay.20
a
b
c
Aqueous solubility (
Clint: intrinsic clearance (
l
g/ml) measured in a lyophilisation solubility assay.21
L/min/mg protein).
l
pound 37 via chromatographic separation of the racemate on a
Chiralcell OD column (Daicel; elution: heptane/ethanol 85:15).
Surprisingly, both enantiomers showed similar EC50-values for
inhibition of GlyT1, whereas the selectivity of the (+)-enantiomer
versus inhibition of GlyT2 was somewhat better (Table 4).
Despite their high lipophilicity (ClogP = 3.8–4.7) and thus low
aqueous solubility, these simple bis-amides display interesting
molecular properties (Table 5). It is interesting to note that the most
active compounds 24, 25 and 13 show low microsomal clearances.
This is in contrast to the less active derivative 8 containing a two
carbon linker which is likely to be metabolically labile. However,
no studies have been performed to identify potential metabolites
of these inhibitors. Membrane permeability20 is high to medium
and most of the compounds show no or minor inhibition of
CYP450 enzymes; all IC50-values for 3A4, 2D6 and 2C9 are
>50
4.9 and 14.7
the representative derivatives 20, 22 and 24 for their activity at the
GABAA receptor; all three compounds were inactive at 3.16 M ver-
sus the benzodiazepine binding site of the rat GABAA 1b3 2, GA-
BAA 2b3 2, GABAA 3b3 2 and GABAA 5b3 2 receptor subtypes.
l
M, with the exception of compound 13 which has an IC50 of
l
M against 2D6 and 2C9, respectively. We also tested
l
c
20. Kansy, M.; Senner, F.; Gubernator, K. J. Med. Chem. 1998, 41, 1007.
21. Compound initially in DMSO solution is lyophilised 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 analyzed by direct UV measurement or
by HPLC-UV.
a
a
c
a
c
a
c
In summary, we report here the discovery of a new and simple
chemotype of GlyT1 inhibitors. Starting from a high throughput hit