Discovery of indolone acetamides as novel SV2A ligands with improved potency toward seizure suppression

Article abstract of DOI:10.1002/cmdc.200900436

(Chemical Equation Presented) Capitalizing on the proven clinical efficacy of levetiracetam as an antiepileptic drug, a drug discovery program lead to the identification of a new generation of SV2A ligands with equal or better tolerability profiles than levetiracetam, and improved potency toward seizure suppression in animal models.

Full text of DOI:10.1002/cmdc.200900436

MED
DOI: 10.1002/cmdc.200900436
Discovery of Indolone Acetamides as Novel SV2A Ligands with Improved
Potency Toward Seizure Suppression
[
a]
[c]
[a]
[a]
[b]
Anne Frycia, Jean-Philippe Starck, Sophie Jadot, Bꢀnꢀdicte Lallemand, Karine Leclercq,
[
a]
[b]
[a]
[a]
[a]
Patrick Lo Brutto, Alain Matagne, Valꢀrie Verbois, Joꢁl Mercier, and Benoit Kenda*
A major goal in epilepsy research is to develop new antiepilep-
tic drugs (AEDs) that combine improved seizure control with
lead to the identification of two compounds currently in clini-
cal development: brivaracetam (3) and seletracetam (4), both
of which are more potent than 2 in vitro toward SV2A and
in vivo as anticonvulsant agents in audiogenic seizure-prone
[1]
enhanced tolerability while avoiding drug–drug interactions.
Although the prognosis for seizure control is acceptable in up
to 70% of patients, approximately 30% suffer from intractable
[16–19]
mice.
(Figure 1)
[
2,3]
pharmaco-resistant epilepsy.
Furthermore, the clinical use of
most older AEDs is hampered by their limited tolerability; this
most commonly consists of CNS-related adverse effects, idio-
syncratic reactions such as skin rashes, and the potential for
[
4]
unfavorable drug–drug interactions. It was previously report-
ed that the AED levetiracetam (2; Keppraꢂ) has a unique brain-
[
5–7]
specific binding site.
This site was recently identified as the
synaptic vesicle protein 2A (SV2A). A strong correlation be-
tween the affinity of levetiracetam analogues for SV2A and
their anti-seizure potency in the audiogenic mouse model of
[
8]
epilepsy has been reported. This suggests that levetirace-
tam’s interaction with SV2A has a major functional role in its
anticonvulsant mechanism of action.
SV2, a protein specific to synaptic vesicles, is a 12-transmem-
brane region glycoprotein present in all neural cells, and it is
[
8–14]
present in three isoforms: SV2A, SV2B, and SV2C.
SV2A is
the most widely distributed isoform and is ubiquitous in the
CNS, but is also present in endocrine cells. Although the exact
molecular role of SV2A is still unknown, it is believed to play a
role in the exocytosis of neurotransmitters and to act as a
Figure 1. Levetiracetam 2, brivaracetam 3, seletracetam 4, and lead com-
pound 9n.
[
9–14]
modulator of vesicle fusion.
Given the proven clinical effi-
Herein we report the synthesis and pharmacological profile
of a new series of potent SV2A ligands starting from the lead
cacy of levetiracetam as an AED, its unique mechanism of
action, and its excellent tolerability, we decided to initiate a
drug discovery program focused on SV2A as a novel molecular
target. The aim was to identify a new generation of SV2A li-
gands with an equal or better tolerability profile than 2 and an
improved potency toward seizure suppression in animal
models.
[20]
compound 9n. This compound, initially synthesized as an
analogue of piracetam (1), was later identified as a weak SV2A
ligand during a high-throughput screen of UCB’s historical
compound collection.
Despite its low affinity for SV2A (pIC : 5.3), the indolone 9n
50
was considered to be a good lead compound based on a
multi-parametric analysis. It showed: 1) favorable in silico prop-
At the outset of our work in the SV2A field, we systematical-
ly investigated the various positions of the pyrrolidone acet-
[21]
erties, 2) a high ligand efficiency index,
and 3) interesting
[
15]
amide scaffold of 2. Among others, we discovered the im-
portance of the carboxamide moiety on 2 and the preferred
pharmacokinetic (PK) properties such as high permeability,
good bioavailability in rat (F>90%) and low potential for inter-
action with cytochrome P450 (CYP450) enzymes (at 50 mm
against isoforms 2D6, 3A4, 2C9, and 2C19) (Table 1). Overall,
the data were very similar to those obtained with levetirace-
tam.
[
15]
substitution position a to the carboxamide.
This research
[a] A. Frycia, S. Jadot, B. Lallemand, P. Lo Brutto, V. Verbois, J. Mercier,
Dr. B. Kenda
Department of Chemistry, UCB Pharma S.A.,
Chemin du Foriest, 1420 Braine l’Alleud (Belgium)
Fax: (+32)2-3862704
Using this information, we initiated a drug discovery pro-
gram aimed at the identification of novel indolone acetamide
derivatives with improved affinity for SV2A and potent anticon-
vulsant properties in vivo, by systematically investigating the
structure–activity relationships around the aromatic ring, the
carboxamide moiety, and the a position (Figure 1). Modifica-
tion of these structural features significantly improved both
the anticonvulsant potency and the margin between impair-
E-mail: benoit.kenda@ucb.com
[b] K. Leclercq, A. Matagne
Department of CNS Research, UCB Pharma S.A.
Chemin du Foriest, 1420 Braine l’Alleud (Belgium)
[c] Dr. J.-P. Starck
Present address: NMR tec, Bld. Sꢀbastien Brandt
Bioparc – Bat. B, 67400 Illkirch Graffenstaden (France)
2
00
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2010, 5, 200 – 205

[
a]
Table 1. In silico, physicochemical, and PK properties of compounds 2 and 9n.
[
b]
3
[c]
ꢀ1
ꢀ1 [d]
ꢀ1 [e]
[g]
Compd
M
r
[Da]
nRotB
PSA [ꢄ ]
CLint [mLmin (mg protein)
]
LogP
Solubility [mgmL
]
Eff_n
(>0.3)
Selectivity
[f]
(
<500)
(<10)
(<90)
(<100)
2
170
190
3
2
59.2
59
<20
<10
ꢀ0.65
>1.5
>1.4
0.63
0.51
0/35
0/35
9
n
0
[
22]
[
a] In silico properties calculated as described by Veber et al. [b] Number of rotatable bonds. [c] Polar surface area. [d] In vitro clearance measured on rat
[
21]
2
NADPH-fortified microsomes. [e] Thermodynamic solubility in H O at pH 7.4. [f] Ligand efficiency number as described by Hopkins et al. [g] Number of
targets with >50% inhibition at 10 mm over a broad receptogram of 35 different CNS-related targets (GPCRs, ions channels, and enzymes).
ment of rotarod performance and clonic seizure suppression in
audiogenic seizure-prone mice. Additional data in secondary
models of epilepsy, as well as PK profiles, are also presented.
Dithiolanes 6 were prepared by acid-catalyzed cyclo-conden-
then tested in vivo in audiogenic seizure-prone mice. In this
model, convulsions are evoked by exposing animals to high-
[35]
frequency sonic stimulation.
This induces three successive
phases of seizure activity: wild running, clonic and tonic con-
vulsions. An effective dose (ED50 value following i.p. administra-
tion with a pretreatment time of 1 h) suppressing clonic con-
vulsions in 50% of the animals was used as the parameter to
compare the potency of seizure protection (see ref. [15] for de-
tails). Secondary epilepsy pharmacology was assessed on
[
23]
sation of isatins 5 with 1,2-ethanedithiol. Alkylation with a-
[
24]
bromoamides 7
and removal of the dithiolane group by
[
25]
treatment with Raney nickel provided indolones 9. This de-
protection reaction suffered from: 1) a lack of reproducibility,
2
3
) the requirement for large amounts of Raney nickel, and
) competitive reduction/dehalogenation of the aromatic ring
[16]
amygdala-kindled rats using known protocols.
substituents during the deprotection step in some cases (even
at temperatures <08C). Compound 8p could not be obtained
by this method because the nitro group was reduced prior to
deprotection. To circumvent these side reactions, direct halo-
genation—using bromine, N-bromosuccinimide, N-chlorosucci-
We initially focused our strategy by screening a diverse
range of substituents on the aromatic ring (Table 2). The affini-
ty toward SV2A was found to depend largely on the position
and nature of the substituent. Small hydrophobic groups, par-
1
2
3
ticularly halogen atoms, at positions 5 (R ), 6 (R ), and 7 (R ) in-
creased the affinity toward SV2A, whereas position 4 was very
sensitive to steric hindrance. Overall, this structure–activity re-
lationship is consistent with that observed in the pyrrolidone
acetamide family (i.e., analogues of compounds 2), for which
substitution at the 4-position of the pyrrolidone moiety (as in
compounds 3 and 4) with hydrophobic groups had a benefi-
[24,26]
nimide, or N-iodosuccinimide—under acidic conditions
of
9
9
n (for compounds 9a, 9c, and 9r) or of 9d (for compound
q) were used to produce the corresponding indolones 9.
Treatment of 9n with nitric acid in trifluoroacetic acid afforded
[
27]
compound 9p. The dibromo compound 9o was obtained
from 9n by treatment with bromine in excess (Scheme 1).
Another way to prepare indolones 9 from isatins was the
two-step procedure of reduction/acylation followed by hydro-
[15]
cial impact on SV2A affinity.
All the compounds active in the SV2A in vitro screen were
tested in vivo in audiogenic seizure-prone mice. In most cases,
[
28–30]
genation on Pd(OH)2.
The intermediate hydroxyindoles 13
1
2
3
were rather unstable and were immediately used in the acyla-
tion step. While this robust procedure has allowed us to pre-
pare 9n on the multi-gram scale, it also suffers from a lack of
selectivity in the presence of halogens on the aromatic ring.
A more versatile and reliable method for the preparation of
indolones 9 is the alkylation of indoles 15 with a-bromoamides
the addition of an alkyl group at R , R , or R (compounds 9g–
9j) only resulted in a modest increase in the in vivo potency
ꢀ
1
relative to the lead compound 9n (ED =360 mmolkg ). This
50
did not correlate with the significant improvement in SV2A af-
finity in vitro, and probably reflects the high clearance of these
compounds due to hepatic metabolism. Indeed, replacing the
7
followed by oxidative bromination with pyridinium bromide
alkyl substituent with a halogen or a CF group (compounds
3
[
24,31]
perbromide in a mixture of tert-butanol.
The obtained 3,3-
9a, 9o, 9c, and 9r) significantly increased SV2A potency
in vivo, which correlates with their improved in vitro affinity.
Compound 9c was identified as the most interesting template
due to its high ligand efficiency index, moderate solubility, and
excellent in vivo anti-seizure potency. Also worth noting is that
the fourth (C4) position of the aromatic ring has been exten-
sively explored by our research group, but did not lead to im-
provement in affinity toward SV2A (data not shown).
dibromoindolones 17 were then reduced by treatment with
Zn/AcOH. The choice of using either isatins or indoles as start-
ing products depended mainly on their commercial availability
or on their synthetic accessibility. Isatins 5g, 5h, 5j, 5m were
[
32,33]
prepared with the Sandmeyer reaction.
The synthesis of
indole 15b was carried out according to published proce-
[
34]
dures. Compound 9v was prepared from 10v by peptidic
coupling with 3-aminophenol. Compound 10v can be ob-
tained by acidic hydrolysis of 9n and subsequent chlorination
with N-chlorosuccinimide in sulfuric acid. Compounds 9 s and
Once the exploration of the aromatic region was complete,
and the chlorophenyl moiety was identified as our preferred
substituent, we sought to investigate the SAR of the “lower”
acetamide moiety (Table 3). Most of our earlier attempts to in-
troduce a substituent at the “3” position of the pyrrolidone
9
t were separated from their enantiomers by chiral chroma-
tography.
The primary in vitro screen consisted of a binding assay with
[15]
moiety did not increase the affinity for SV2A. On the other
hand, we have described that the introduction of a single
[
7]
a tritiated analogue of 2. Ligands with a pIC50 value >4 were
ChemMedChem 2010, 5, 200 – 205
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
201

MED
Scheme 1. Reagents and conditions: a) BF
3
·Et
2
O, AcOH, 608C; b) NaH, DMF, 0–408C; c) Raney Ni, THF, RT; d) NaBH
O, RT; h) Zn, AcOH; i) PS–dicyclohexylcarbodiimide, PS–diisopropylethylamine,
(90%), RT; k) N-bromosuccinimide, CF COOH (cat), CH COOH (cat),
CN, 08C!RT; l) N-iodosuccinimide, CF
COOH, 08C!RT; o) HCl (5n), reflux.
4
, MeOH, 08C!RT; e) Ac
2
O, 4-dimethylamino-
pyridine; f) Pd(OH)
CH Cl /DMF (1:1), RT; j) N-chlorosuccinimide, H
RT; m) Br (2 equiv), EtOH, RT; n) HNO , CF
2
, H
2
, EtOH, RT; g) pyridinium bromide perbromide, tBuOH/H
2
2
2
2
SO
4
3
3
3
2
3
3
short alkyl chain (methyl or ethyl) a to the carboxamide of pi-
racetam (1) leads to an increase in affinity (and in vivo anti-
seizure activity) in a stereoselective manner, probably reflecting
a conformational effect stabilizing the bioactive conforma-
SV2A but a favorable lead profile, we built the structure–activi-
ty relationship described above. Two novel ligands with high
affinity (compounds 9c and 9t) were identified based on their
high affinity for SV2A, high ligand efficiency index, and potent
in vivo anti-seizure properties. Both compounds showed im-
proved activity—10- to 40-fold—over that of levetiracetam in
vitro and in our primary in vivo epilepsy model. Compound 9t
was identified as the more interesting compound, and was se-
lected for further profiling in secondary epilepsy pharmacolo-
gy, PK, and acute toxicology.
[
15]
tion.
Using both the 5-chloro- and 5-bromoindolone sub-
stituent, we again observed a similar improvement in the in vi-
tro potency, with the “2”-S enantiomer (9t) being the eutomer
with high stereoselectivity (DpIC >2log between “2”-R and
50
“
2”-S). Affinity is optimal with methyl and ethyl substituents,
and decreases with longer alkyl chains (data not shown).
In vivo, an impressive anti-seizure potency (ED =
The acetamide 9t has very favorable physicochemical pa-
rameters and is characterized by moderate water solubility and
relatively modest lipophilicity (Table 4). In vitro, 9t is metabol-
ically stable with low intrinsic clearance on NADPH-fortified
50
ꢀ1
3
mmolkg ) was observed with compound 9t, which is 100-
fold more active than the lead compound 9n. The surprisingly
modest in vivo activity of the analogue 9u was correlated with
its higher microsomal clearance (data not shown).
ꢀ
1
ꢀ1 [36]
liver microsomes [CL <5 mLmin (mg protein) ]. On Caco-
int
Using high-throughput synthetic organic methods, we thor-
oughly explored substitution around the carboxamide moiety.
Although tolerated, mono- and disubstitution of the carboxa-
mide nitrogen atom by alkyl, aryl, or heteroaryl groups consid-
erably decreases the SV2A affinity, in line with our previous ob-
2 cells, the compounds show good permeability (P
>
apps
ꢀ
6
ꢀ1 [37]
10 cms ). In vivo PK studies in rats confirmed the high
bioavailability together with a low total clearance and a half-
life within the range of levetiracetam 2 (Table 4). No relevant
inhibition of CYP450 was identified at 50 mm (isoforms 2D6,
3A4, 2C9, and 2C19).
[
15]
servation in the pyrrolidone acetamide series.
As a conclusion of our medicinal chemistry efforts, and start-
In a range of secondary epilepsy models, compound 9t dis-
played more complete seizure suppression than levetiracetam
ing from the lead 9n, characterized by modest affinity for
2
02
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ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2010, 5, 200 – 205

Table 2. In vitro and in vivo pharmacological data for levetiracetam and
its analogues.
Table 3. In vitro and in vivo pharmacological data for various carboxa-
mide and a-substituted compounds.
1
2
3
1
4
5
[a]
Compd
R
R
R
SV2A
pIC50
ED50 Audio
Compd
R
R
R
Stereo
SV2A
pIC50
ED50 Audio
[mmolkg ]
[
a]
ꢀ1 [b]
[b]
ꢀ1 [c]
[mmolkg
]
2
3
4
–
–
–
H
Br
CF
Cl
F
H
H
Et
iPr
Me
nPr
OCF
Me
Me
Br
NO
Cl
I
–
–
–
–
–
–
6.1
7.0
7.1
5.3
7.3
6.7
7
180 (143–283)
14 (6.6–24)
0.17 (0.09–0.29)
2
–
–
–
H
H
H
H
–
–
6.1
7.3
7.6
7
7.4
7.3
6.3
180 (143–283)
9a
9s
9c
9t
9u
9v
Br
Br
Cl
Cl
Cl
Cl
H
Me
H
Me
Et
18
10
5
[
d]
R or S
9
9
9
9
9
9
9
9
9
n
a
b
c
e
d
f
H
H
H
H
H
H
Cl
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
Me
H
Br
H
F
360
18
56
5
80
>1000
640
84
–
[
e]
S
3 (3.7–5.4)
[f]
3
H
R and S
42
–
H
3-OH-C
6
H
4
–
6
[
[
[
a] Stereochemistry data; enantiomeric excess values are >98%.
5.3
6.1
6.5
6.4
6
6.5
6.3
6
6.6
7
6
6.9
7.7
b] pIC50 =ꢀlog of the unlabeled drug concentration that inhibits
3
H]levetiracetam or an analogue as described in references [5–7]; all
g
h
values represent the mean of two independent determinations; each
pIC50 value lies within 0.2 log units of the mean. [c] Dose that protects
0% of audiogenic seizure-prone mice against clonic convulsions follow-
ing i.p. administration at 1 h pre-treatment time; values in parentheses in-
dicate 95% confidence level. [d] l isomer with >96% ee. [e] Absolute ste-
reochemistry defined by X-ray crystallography. [f] Racemic mixture.
320
130
320
120
9
9
9
9
i
j
k
l
5
3
[c]
1000
[c]
9
9
m
o
320
8
9
9
p
q
2
1000
80
5
9
r
H
Table 4. Pharmacokinetics and physicochemical parameters for com-
pound 9t.
[
[
a] pIC50 =ꢀlog of the unlabeled drug concentration that inhibits
3
H]levetiracetam or an analogue as described in references [5–7]; all
values represent the mean of two independent determinations; each
pIC50 value lies within 0.2 log units of the mean. [b] Dose that protects
Physicochemistry
In vivo PK (Rat)
[
a]
50% of audiogenic seizure-prone mice against clonic convulsions follow-
LogD
Solubility
[mgmL
1
Dose
[mgkg
1
t1/2
[h]
1.62
tmax
CL
Foral
[%]
79
ꢀ
1
ꢀ1
ꢀ1
ꢀ1
ing i.p. administration at 1 h pre-treatment time; values in parentheses in-
dicate 95% confidence level. [c] Compound inactive at the indicated
dose.
]
]
[h]
0.3
[mLmin kg
2.6
]
1.23
[
2
a] LogP octanol/H O; buffer: PBS, pH 7.4.
[
16]
(
2). As an example, in fully amygdala-kindled rats,
9t in-
duced a significant decrease in motor-seizure severity from a
Several novel ligands with a high affinity for SV2A have
ꢀ1
dose of 2.3 mgkg , whereas 2 induced a similar effect at a
been identified. The medicinal chemistry program has been
particularly successful in achieving a 100-fold increase in bind-
ing potency toward SV2A and up to a 40-fold improvement in
in vivo pharmacology over the initial lead 9n. In a range of
secondary epilepsy models, one of the more interesting com-
pounds, 9t, displays more complete seizure suppression than
levetiracetam (2), as well as an outstanding safety margin. This
illustrates once again the high potential of SV2A as a target for
the discovery of new AEDs dedicated to the refractory popula-
ꢀ
1
dose of 170 mgkg (Figure 2). Compound 9t also significantly
decreased the after-discharge duration (ADD) from a dose of
ꢀ
1
7
8.4 mgkg , whereas 2 was inactive on this parameter at up
ꢀ
1
to 1700 mgkg (Figure 2).
The clinical benefit of new AEDs depends on their therapeu-
tic index, that is, the margin between the doses that induce
therapeutic and CNS-related adverse effects. When quantifying
adverse effects by a TD value in the rotarod test in amygda-
50
[
38]
[8]
la-kindled rats, and dividing it by the ED50 value for protec-
tion against generalized seizures in the same animals, 9t
showed a higher safety margin (~5.5) than did levetiracetam
tion of epileptic patients.
Acknowledgements
(
2) (~2), but similar to that observed with brivaracetam (3;
[16]
Figure 3).
The authors are grateful to Z. Povegliano, A. Gallisz, C. Chaussee,
M. Grossman, M. S. Declercq, D. Mertens, and B. Vivier for their
skillful assistance; Dr. E. Schenkel, Dr. L. Quere, and L. Ellens for
lipophilicity and solubility measurements; E. Cavoy and Dr. Pinilla
for chromatographic purifications; Dr. R. Dieden, Dr. B. Mathieu,
and A. Fauconnier for analytical assistance; Dr. J.-M. Nicolas, M.
The outstanding results in pharmacology presented above,
especially in comparison with other marketed antiepileptic
[
39,40]
drugs,
makes compound 9t an interesting potential AED
candidate. This is further confirmed by the fact that 9t has no
marked effect on cardiovascular, respiratory, GI tract, and CNS
function (data not shown).
ChemMedChem 2010, 5, 200 – 205
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
203

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Figure 2. Comparison of seizure protection in amygdala-kindled rats by A) levetiracetam 2 [values represent the mean ꢁSD (n=22)] and B) compound 9t
[values represent the mean ꢁSD (n=8)]; *p<0.05 with respect to pre-drug value.
[
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