Ethyl (3s,4aR,6S,8aR)-6-(4-ethoxycar-bonylimidazol-1-ylmethyl) decahydroiso-quinoline-3-carboxylic ester: A prodrug of a GluR5 kainate receptor antagonist active in two animal models of acute migraine

Article abstract of DOI:10.1021/jm025548q

Amino diacid 3, a highly selective competitive GluR5 kainate receptor antagonist, exhibited high GluR5 receptor affinity and selectivity over other glutamate receptors. Its diethyl ester prodrug 4 was orally active in two models of migraine: the neurogeni

Full text of DOI:10.1021/jm025548q

J . Med. Chem. 2002, 45, 4383-4386
4383
Ch a r t 1
Eth yl (3S,4a R,6S,8a R)-6-(4-Eth oxyca r -
bon ylim id a zol-1-ylm eth yl)d eca h yd r oiso-
qu in olin e-3-ca r boxylic Ester : A P r od r u g
of a Glu R5 Ka in a te Recep tor An ta gon ist
Active in Tw o An im a l Mod els of Acu te
Migr a in e
Sandra A. Filla,*,† Mark A. Winter,†
Kirk W. J ohnson,† David Bleakman,†
Michael G. Bell,† Thomas J . Bleisch,†
Ana M. Castan˜o,‡ Amy Clemens-Smith,†
Miriam del Prado,‡ Donna K. Dieckman,†
Esteban Dominguez,‡ Ana Escribano,‡ Ken H. Ho,§,|
Kevin J . Hudziak,† Mary A. Katofiasc,†
J ose A. Martinez-Perez,‡ Ana Mateo,‡
Brian M. Mathes,† Edward L. Mattiuz,†
Ann Marie L. Ogden,† Lee A. Phebus,†
Douglas R. Stack,† Robert E. Stratford,† and
Paul L. Ornstein†
Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, Indiana, 46285, Centro de Investigacio´n Lilly,
S. A. Avda. De la Industria 30, 28108-Alcobendas, Madrid,
Spain, and Allelix Biopharmaceuticals, Mississauga,
Ontario L4V1P1, Canada
tive GluR5 KA receptor antagonist 1 (LY382884)6 was
active in an animal model of persistent pain,7 and Sang
and co-workers showed that 2 (LY293558),8 a competi-
tive AMPA/KA antagonist, significantly reduced pain
intensity and unpleasantness in an experimentally
induced human pain study and reduced clinical pain in
a study of evoked pain (Chart 1).9
Received J une 4, 2002
Abstr a ct: Amino diacid 3, a highly selective competitive
GluR5 kainate receptor antagonist, exhibited high GluR5
receptor affinity and selectivity over other glutamate receptors.
Its diethyl ester prodrug 4 was orally active in two models of
migraine: the neurogenic dural plasma protein extravasation
model and the nucleus caudalis c-fos expression model. These
data suggest that a GluR5 kainate receptor antagonist might
be an efficacious antimigraine therapy with a novel mechanism
of action.
More recently, glutamate receptors have been linked
with migraine headache. Investigators identified what
appeared to be GluR5 KA receptors in the trigeminal
ganglion neurons,10 where pseudounipolar neurons in-
nervating the meninges originate. Additionally, plasma
levels of glutamate were elevated in patients with a
history of migraine headaches, and glutamate levels
were further raised in these patients during a migraine
attack.11 Recently, glutamate receptors were reported
to modulate capsaicin-induced c-fos expression in the
trigeminal nucleus caudalis,12 an established model of
migraine.13 These data suggested that NMDA and
AMPA, but not KA, receptor antagonists and mGluR
receptor agonists might be effective acute treatments
for migraine pain via a nonserotonergic mechanism of
action.14 In contrast, we propose that GluR5 KA receptor
antagonists might be potential antimigraine agents. We
describe here the in vitro activity of (3S,4aR,6S,8aR)-
6-(4-carboxyimidazol-1-ylmethyl)decahydroisoquinoline-
3-carboxylic acid 3, a potent and selective GluR5 KA
receptor antagonist, and the oral activity of diethyl ester
4, in two animal models of migraine.
Glutamic acid is the primary excitatory amino acid
in the central nervous system. It mediates neuronal
effects through two types of receptors: G-protein-
coupled metabotropic glutamate receptors and ionotro-
pic glutamate receptors, which are ligand-gated ion
channels. The ionotropic receptors are defined, on the
basis of subtype selective agonists, as N-methyl-D-
aspartate (NMDA), R-amino-3-hydroxy-5-methyl-4-isox-
azolepropionic acid (AMPA), or kainate (KA).1 Recent
molecular biology studies have further divided the
AMPA subtype into GluR1-4, and the KA subtype into
GluR5-7 and KA1 and KA2 subunits.2
Several studies have implicated KA receptors, specif-
ically the GluR5 receptor subtype, in pain transmission.3
C-fiber primary afferents, which possess KA receptors,4
transfer nociceptive information from the periphery to
the spinal cord. The biophysical and pharmacological
profile of KA receptors in the dorsal root ganglion
(DRG), cell bodies in the dorsal root associated with
primary afferent neurons, suggests that they are GluR5
receptors.5 Simmons et al. demonstrated that the selec-
The preparation of compounds 3 and 4 is outlined in
Scheme 1. Both compounds were derived from hy-
droxymethyl intermediate 5, the synthesis of which has
previously been described.15 Conversion to nosylate 6,
followed by alkylation with ethyl imidazole-4-carboxy-
late, provided a 1:1 mixture of isomers 7 and 8, which
were separated by column chromatography. Treatment
of the desired regioisomer 8 with TMSI selectively
removed the methyl carbamate protecting group.
* To whom correspondence should be addressed. Phone: 317-277-
2789. Fax: 317-276-7600. E-mail: filla_sandra_a@lilly.com.
† Lilly Research Laboratories.
‡ Centro de Investigacio´n Lilly.
The resulting amine was then converted to the
diethyl ester dihydrochloride salt 4. Additionally, ester
§ Allelix Biopharmaceuticals.
| Present address: Lilly Research Laboratories.
10.1021/jm025548q CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/24/2002

4384 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 20
Letters
Ta ble 1. In Vitro Binding Affinities of AMPA/KA Antagonists for Recombinant Human AMPA and KA Receptorsa
compd
GluR1b
GluR2b
GluR3b
GluR4b
GluR5c
GluR6c
GluR7c
GluR6/KA2c
2
3
9
9.2 ( 3.9
134 ( 19
1.6 ( 0.9
3.2 ( 0.3
117 ( 16
0.26 ( 0.04
32 ( 5
247 ( 33
0.9 ( 0.3
50 ( 13
262 ( 61
0.6 ( 0.9
4.2 ( 0.3
0.156 ( 0.075
11.6 ( 4.4
>100
>100
48.5 ( 1.9
23.9 ( 6.9
>100
236 ( 27
>100
>1000
13.2 ( 1.9
a
Affinities for receptors (Ki, µM) were determined in vitro by radioligand binding assays using HEK 293 cell membranes expressing
the appropriate human AMPA or KA receptor.16 Each value is the mean ( SEM of at least three determinations. [3H]AMPA was used
b
as the high-affinity radioligand. c [3H]KA was used as the high-affinity radioligand.
Sch em e 1a
a
Conditions: (a) NsCl, Et3N, CH2Cl2, room temp (68%); (b) ethyl
imidazole-4-carboxylate, NaH, DMF, room temp (40%); (c) (i)
TMSI, CH2Cl2, room temp; (ii) HCl/Et2O, room temp (72%, two
steps); (d) 5 N HCl, 75 °C (85%).
F igu r e 1. Inhibition of glutamate (200 µM)-invoked calcium
influx by 3 in the human GluR5(Q) receptor stably transfected
in HEK293 cells, with mean value ( SEM for n ) 3.
deprotection of 4 by heating in 5 N HCl provided amino
diacid 3.
Amino diacid 3 was evaluated in ligand binding
studies for its ability to displace binding of [3H]AMPA
to recombinant human AMPA receptors and [3H]KA to
recombinant human KA receptors expressed in HEK
293 cell membranes.16 Table 1 shows the affinity of 3
for the various cloned human AMPA and KA receptors
compared with competitive AMPA/KA antagonist 2 and
the quinoxalidinedione AMPA/KA antagonist 9 (NBQX),
a standard tool used in the study of AMPA receptors.17
Compound 2 displaced binding to AMPA and GluR5
receptors but not other KA receptor subunits. As
reported, 9 displaced radioligand binding at AMPA and
to a lesser extent KA receptors and showed no selectivity
for the GluR5 receptor. In contrast, 3 exhibited high
F igu r e 2. Effects of 3 on the concentration-effect curve of
glutamate in the human GluR5(Q) receptor stably transfected
affinity for the KA GluR5 receptor, with greater than
300-fold selectivity over other KA and AMPA receptors.
Compound 3 behaved as an antagonist, inhibiting
glutamate-evoked calcium influx in the human GluR5-
(Q) receptor stably transfected in HEK293 cell mem-
branes, with an estimated IC50 of 1.18 ( 0.22 µM
(Figure 1).16,18 Consistent with competitive antagonists
in this assay, 3 produced rightward shifts in the
glutamate concentration-effect curves, with an esti-
mated KB of 0.259 ( 0.063 µM (Figure 2).19 In addition,
the inhibitory activity of 3 was evaluated at GluR5 KA
receptors found in rat neonatal DRG neurons, using
whole cell voltage clamp recordings.20 Its IC50 value,
determined against a screening concentration of 30 µM
KA, was estimated to be 0.85 ( 0.11 µM. On the basis
of these data, we characterized 3 as a highly selective,
competitive GluR5 KA receptor antagonist.
in HEK293 cells: (0) glutamate (estimated EC50 of 54.96 (
8.28 µM); (2) glutamate + 300 nM 3; (O) glutamate + 3 µM 3.
Included is the mean value ( SEM for n ) 3.
plasma 1 h following a 30 mg/kg oral dose.21 The plasma
half-life of 3 following oral administration of 4 ranged
from 2 to 3 h, and its oral biovailability, administered
as its diethyl ester 4, was determined to be 50%. On
the basis of these results, we concluded that diethyl
ester 4 would act as a prodrug of amino diacid 3.
The neurogenic dural plasma protein extravasation
(PPE) model, which examines the inhibition of neu-
rotransmitter release from the peripheral branches of
trigeminal sensory neurons following activation of the
trigeminal nerve, is a widely accepted model of acute
migraine.22 Compounds with demonstrated clinical ef-
ficacy, such as sumatriptan, zolmitriptan, ergotamine,
and rizatriptan (10), were effective at blocking plasma
extravasation in this model.23 The efficacy of 4 in the
PPE model was compared to that of 5-HT1 receptor
agonist 10 following oral administration.24 Compound
4, administered orally to fasted Wistar rats 1 h prior to
trigeminal stimulation, decreased extravasation in this
We evaluated the oral efficacy of this novel GluR5 KA
receptor antagonist in two animal models of migraine.
Parent amino diacid 3 itself exhibited poor oral bio-
availability in rat; consequently we evaluated diester 4
as a potential prodrug of 3. We did not detect 4 in rat

Letters
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 20 4385
F igu r e 3. Dose-response curves of 4 and 10 in the PPE
model after oral administration: (2) vehicle; (b) 4; (0) 10.
Values are the mean ratio of Evan’s Blue dye extravasation
in the stimulated side of the dura to that in the unstimulated
side ((SEM) for n ) 3-6. Asterisks denote a significant
difference from the vehicle group (P < 0.05).
F igu r e 4. Comparison of 4 and 10 in the suppression of c-fos
expression in the rat nucleus caudalis ipsilateral to trigeminal
ganglion stimulation (V ) vehicle). For each animal, 10-15
sections were analyzed to provide an average number of
stained cells per section. These averages were combined for
vehicle and compound pretreated animals (n ) 5-22 animals/
group). Asterisks denote a significant difference from the
respective vehicle group (P < 0.05).
model in a dose-related manner, with an estimated ID50
of 100 pg/kg (determined 15 min after stimulation).
Compound 10, evaluated in the identical manner as 4,
had an estimated ID50 of 8 pg/kg (Figure 3). In addition,
parent amino diacid 3 itself was evaluated 15 min
following intravenous administration. Compound 3,
administered intravenously 10 min prior to trigeminal
stimulation, decreased extravasation in a dose-related
manner with an estimated ID50 of 0.03 pg/kg (data not
shown). These data further supported our hypothesis
that 4 was acting as a prodrug of 3.
We also evaluated diester 4 in the nucleus caudalus
c-fos expression model, which examines the inhibition
of central neurotransmitter release and subsequent
nociceptive signaling to higher brain centers, where pain
is perceived. Unilateral electrical stimulation of the
trigeminal sensory neurons induces ipsilateral Fos
protein expression that has been used as a marker of
neuronal activity and subsequently as an index of
migraine-like pain transmission to the central nervous
system.18,25 As shown in Figure 4, 4 was comparable to
10 in decreasing the number of brainstem nucleus
caudalis cells staining for Fos protein expression ipsi-
lateral to the stimulation. One hour of oral pretreatment
with 10 mg/kg dose of 4 produced an approximate 30%
decrease in central Fos expression, compared to a 1 or
3 mg/kg dose of 10 to produce a similar effect.
Both 4 and 10 were considerably more potent in the
PPE model than in the c-fos expression assay. This
difference is often observed between the two models,
regardless of the pharmacological mechanism of action
of the test compound. The PPE model most likely
examines the inhibition of neurotransmitter release in
the periphery, whereas the c-fos assay is assessing
inhibition of central neurotransmitter release. Thus, the
degree of central penetration of a compound could cause
a difference in potency between the two models. Despite
the extreme potency of compounds in the PPE model,
an excellent correlation existed between potency in the
PPE model and GluR5 KA antagonist activity (data not
shown).
established models of migraine. On the basis of these
data, we propose that 3, a selective, competitive GluR5
KA receptor antagonist, may be clinically effective in
treating acute migraine pain via a nonserotonergic
mechanism of action, representing a significant break-
through in the search for new, safe therapies for
migraine.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, including analytical and spectral data, for the prepa-
ration of compounds 3, 4, 6, and 8, as well as experimental
details for the functional studies in recombinant human GluR5
KA receptors and for the nucleus caudalis c-fos expression
model. This material is available free of charge via the Internet
at http://pubs.acs.org.
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