Discovery of orally efficacious tetracyclic metabotropic glutamate receptor 1 (mGluR1) antagonists for the treatment of chronic pain

Article abstract of DOI:10.1021/jm070590c

Metabotropic glutamate receptor 1 (mGluR1) plays important roles in the neurotransmission and pathogenesis of several neurological disorders, including chronic pain. Antagonists of mGlur1 are suggested to be useful for the treatment of pain. Herein, we re

Full text of DOI:10.1021/jm070590c

5550
J. Med. Chem. 2007, 50, 5550-5553
Discovery of Orally Efficacious Tetracyclic
Metabotropic Glutamate Receptor 1 (mGluR1)
Antagonists for the Treatment of Chronic Pain
Wen-Lian Wu,*,† Duane A. Burnett,† Martin Domalski,†
William J. Greenlee,† Cheng Li,† Rosalia Bertorelli,‡
Silva Fredduzzi,‡ Gianluca Lozza,‡ Alessio Veltri,‡ and
Angelo Reggiani‡
Schering-Plough Research Institute, 2015 Galloping Hill Road,
Kenilworth, New Jersey 07033, and Schering-Plough Research
Institute, San Raffaele Science Park, Via Olgettina, 58,
20132 Milan, Italy
Figure 1. Representative mGluR1 antagonists.
ReceiVed May 21, 2007
Abstract: Metabotropic glutamate receptor 1 (mGluR1) plays important
roles in the neurotransmission and pathogenesis of several neurological
disorders, including chronic pain. Antagonists of mGlur1 are suggested
to be useful for the treatment of pain. Herein, we report the discovery
of a novel series of tetracyclic mGluR1 antagonists, such as 23c and
23e, with oral efficacy of ED50 of 8 and 5.1 mg/kg, respectively, in rat
spinal nerve ligation neuropathic pain model.
Figure 2. Lead compound and design of the tetracyclic analogues.
demethylation and O-demethylation in a rapid rat pharmaco-
kinetic study (AUC0-6h ) 1927 nM‚h, AUC0-6h (M-14) ) 1337
nM‚h), after oral administration at a dosage of 10 mg/kg. In
the current investigation, we endeavored to improve the
metabolic stability of this compound class and ultimately to
achieve novel and potent mGluR1 antagonists. As depicted in
Figure 2, our design strategy was based on an observation that
bromide 6 (h-mGluR1 IC50 ) 5.9 nM) was equipotent with lead
5.8 Conformational restriction imposed by connecting the two
substituents to form a five-membered or six-membered hetero-
cycle fused to the pyridine ring led to novel tetracyclic
analogues. In so doing, the metabolically labile dimethylamino
group was replaced with a series of heterocycles.
The synthesis of the pyrrolo analogues 11a-c is outlined in
Scheme 1. Treatment of 7a7b with ammonium acetate gave
4-amino compound 8a, which was converted to its bromide 9a.9
Palladium-mediated cross-coupling reaction of 9a and ethoxy-
vinyltributyltin provided 10a, which was subsequently hydro-
lyzed to furnish 11a.10 The corresponding 4-methoxy analogue
11c was prepared in a similar way. The synthesis of 11b was
achieved by a modified approach. Cross-coupling reaction of
9b and allyltributyltin gave 10b;11 subsequent oxidative cleavage
produced an aldehyde intermediate, which spontaneously formed
11b.
Compounds 14a and 14b were prepared via the syntheses
depicted in Scheme 2. Nitration of 126d,7b in refluxing TFA took
place selectively on the pyridine ring, yielding 13a and 13b.
The exact mechanism of the N-demethylation is not clear. Under
prolonged heating, the reaction proceeded to completion,
yielding 13a almost exclusively.12 Subsequent reduction of the
nitro groups of 13a and 13b followed by ring closure led to
14a and 14b, respectively.
The indazole analogues 18a and 18b were synthesized
utilizing intermediates 7a and 7b as scaffolds,7b respectively,
as illustrated in Scheme 3. Removal of the Me group of 7b
gave 4-hydroxypyridine 15b; bromination followed by replace-
ment of the hydroxyl group with chloro substituent afforded
16b.13 Exchange of the bromo substituent to a vinyl group was
achieved by a cross-coupling reaction. Oxidative cleavage of
the vinyl group provided an aldehyde intermediate, which was
Glutamate is the major excitatory neurotransmitter in the
mammalian central nervous system. Glutamate synaptic re-
sponses in the central nervous system are mediated via activation
of two families of receptors: ionotropic glutamate receptors and
metabotropic glutamate receptors (mGluRs). The G-protein-
coupled mGlu receptors are divided into three different groups,
group I (mGluR1 and mGluR5), group II (mGluR2 and
mGluR3), and group III (mGluR4, mGluR7 and mGluR8), based
on structural homology, pharmacology, and signal transduction
mechanisms.1 Group I receptors (mGluR1 and mGluR5) play a
key role in the central sensitization of pain, in addition to a
variety of functions with potential implications in neurological
and psychiatric disorders.2 A number of behavioral and elec-
trophysiological studies have demonstrated a specific role for
group I mGluRs, and in particular mGluR1 receptors, in
nociceptive processing in the CNS, including mechanisms of
hyperalgesia and inflammation.3 The intrinsic activation of spinal
mGluR1 in chronic nociception has been demonstrated using
antagonists, antibodies, and antisense oligonucleotides. Intra-
thecal administration of an mGluR1 antagonist produced anti-
nociceptive effects in the second phase of formalin-induced
nociceptive behavior.4 There is mounting evidence to suggest
use of mGluR1 antagonists for the treatment of chronic pain.5
Several groups have reported a variety of structurally diverse
mGluR1 antagonists, such as 1 (LY 456066),6a 2,6b 3 (JNJ
16259685),6c 4 (A-841720),6d and other small molecules.6e,f
Particularly, the publication of tricyclic 4, derived from a
strikingly similar lead series as ours, from Abbott laboratories,
prompted us to disclose our novel tetracyclic mGluR1 antago-
nists.
Our lead compound 5 (Figure 2), which originated from the
public domain,7a emerged as a potent mGluR1 antagonist in
our screening program.7b Despite its favorable overall pharma-
cological properties, it was deemed unsuitable as a clinical
candidate. Moreover, it proved to undergo extensive N-
* To whom correspondence should be addressed. Phone: (908) 740-
6525. Fax: (908) 740-7164. E-mail: wen-lian.wu@spcorp.com.
† Schering-Plough Research Institute, NJ.
‡ Schering-Plough Research Institute, Italy.
10.1021/jm070590c CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/11/2007

Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23 5551
Scheme 5a
Scheme 1a
a Reagents and conditions: (a) hydroxyethylamine, MeCN, 100 °C, 1
day, 80% (22e); (b) Pd(OAc)2, racemic 2-(di-tert-butylphosphino)-1,1′-
binaphthyl, Cs2CO3, toluene, 125 °C, 20 h, 37% (23e).
a Reagents and conditions: (a) NH4OAc, 130 °C, neat, ∼60% (8a); (b)
Br2, AcOH, 87% (9a); (c) ethoxyvinyltributyltin, Pd(PPh3)4, DIEA, 180
°C (microwave), 20 min; (d) allyltributyltin, Pd(PPh3)4, DIEA, 175 °C
(microwave), 30 min, 37% (10b); (e) HCl, THF, 51% (9c-11c); (f) OsO4
(cat.), NMO, 29%; (g) NaIO4, H2O, 86%.
Table 1. In Vitro Biological Data
IC50 (nM)a,b
compd
mGluR1
mGluR5
rat Ki (nM)a,c
5
9.5
0.7
0.4
4.9
6.0
10000
>1000
1.7%
>10000
-1.7%
0.15%
5%
-12%
-10%
-2%
-8%
702
7.9
16.9
2.4
Scheme 2a
11a
11b
11c
14a
14b
18a
18b
19
28.6
10.8
103.5
17.8
19.6
1000
788
1000
0.5
9.8
16.8
37.6
541
636
446
2.2
5.3
2.5
2.4
2.9
a Reagents and conditions: (a) HNO3, TFA, reflux, 8 h, 75% (13a); or
1 h, 31% (13b); (b) SnCl2, HCl; (c) HCOOH, o-xylene, heat, 9% (14a);
70% (14b) in two steps.
20
21
23a
23b
23c
23d
23e
23f
23g
23h
23i
609
0.6
1.0
0.3
0.4
9.1
0.5
1.5
0.2
Scheme 3a
>1000
>1000
>1000
>1000
>1000
>1000
>1000
24.4
12
2.2
1.4
a The IC50 and Ki data are an average of at least three measurements,
performed on human mGlu1/5 and rat mGlu1 receptors, respectively. The
standard error was 10%, and variability was less than 2-fold from assay to
assay. b Data for inhibition of radioligand binding. % indicates percent
inhibition at 1 µM. c See ref 19.
a Reagents and conditions: (a) BBr3, DCM, -78 °C, 78% (15a); (b)
Br2, AcOH, room temp; (c) POCl3, reflux, 94% (16b, in two-step); (d)
vinyltributyltin, Pd(PPh3)4, DIEA, microwave, 140 °C, 40 min, 37%; (e)
OsO4 (cat.), NaIO4, 68%; (f) NH2NH2, t-BuOH, 70 °C, 23%.
The morpholine analogues 23a-i were prepared according
to Scheme 5. Compound 16b was treated with hydroxylamine
to give intermediate 22b (R ) H) in high yield. Subsequent
intramolecular C-O bond formation under Buchwald conditions
led to analogue 23e (X ) Cl, R ) H).16 Related morpholino
analogues 23 were obtained using analogous chemistry.
The above-mentioned tetracyclic analogues were assayed on
human and mGlu1 receptor in a FLIPR assay and in a rat
receptor binding assay,17 and the data are summarized in Table
1.
Scheme 4a
The three pyrrolo analogues (11a-c) are all very potent and
selective mGluR1 antagonists. Encouraged by this initial suc-
cess, we next examined other isosteric five-membered hetero-
cycles. As revealed in Table 1, imidazole analogue 14a exhibited
potency comparable to lead 5, though 15-fold less than the
corresponding pyrrolo compound 11b. Interestingly, its N-Me
derivative 14b retained similar human mGluR1 potency but
much less rat mGluR1 activity. The two indazole analogues (18a
and 18b) displayed reduced mGluR1 activity by severalfold,
suggesting the 2-position had limited tolerance. Indeed, large
substituents as in 19-21 resulted in dramatic loss of mGluR1
potency.
a Reagents and conditions: (a) potassium xanthate, DMF, 160 °C, 74%;
(b) K2CO3, MeI, DMF, room temp, 76%; (c) NaOMe, DMF, room temp,
48%.
treated with hydrazine to furnish 18b.14 Compound 18a was
prepared accordingly.
The syntheses of 19-21 are shown in Scheme 4. Heating 9a
with potassium xanthate afforded 19, which in turn was easily
methylated to give 20. Finally, hydrolysis of 20 was effected
by treatment with sodium methoxide in DMF to furnish 21.15
It was increasingly apparent that all the flat fused tetracyclic
analogues mentioned above have poor water solubility, presum-
ably driven by intermolecular π-stacking of the flat aromatic

5552 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23
Table 2. PK Profile and in Vivo Activity of Selected Compounds
Letters
24) and 5.1 (95% confidence interval of 0.9-28.2) mg/kg.
Compounds 23h and 23i also showed significant activity at dose
of 10 mg/kg (the ED50 values were not determined).
AUC0-6h
Tmax
Cmax
rat SNL
rat SNL
compd
(nM‚h)a
(h)a
(nM)a
PWT (g)b
MPE (%)b
In summary, using heterocycles as surrogates for the meta-
bolically labile dimethylamino group of the lead 5, we have
succeeded in the identification of three distinctive types of
tetracyclic mGluR1 antagonists, namely, indoles 11a-c, imi-
dazole 14a, and morpholine analogues 23a-i. Among them,
especially remarkable are the mopholine analogues with im-
proved pharmacokinetic profiles (23h and 23i) and excellent
in vivo activity in rat SNL model (23c and 23e). The high
potency and subtype selectivities, combined with pronounced
oral efficacy, rendered these mGluR1 antagonists valuable tools
for in vivo proof of principle animal studies in neuropathic pain.
Further investigation will be reported in due course.
5
1927
35
18
1325
77
1563
366
8434
5187
0.5
0.5
0.5
2
1
2
1
2
0.5
564
71
37
394
70
467
198
2046
1425
13.2 ( 1.3
87 ( 9
11a
11b
11c
23a
23c
23e
23h
23i
6.6 ( 2.3
39 ( 16
8.5 ( 1.6
11.8 ( 1.6
7.7 ( 1.5
10.9 ( 1.6
50 ( 12
73 ( 13
44 ( 12
68 ( 12
a Data are from pooled samples from two rats (n ) 2, dosed at 10 mg/
kg, po) in cassette-accelerated rapid rat protocol as described in ref 18.
b Data are the mean ( SE from 8 to 10 rats dosed at 10 mg/kg, po, and
they are expressed as paw withdrawal threshold (PWT, g). MPE (maximal
percentage of effect) was also reported. For all experimental details see ref
19.
Acknowledgment. The authors thank Dr. Deen Tulshian and
Dr. John Hunter for their support and helpful discussions. We
gratefully acknowledge Lisa Broske’s group for animal dosing
and Sam Wainhaus’ group for the PK sample analysis. We thank
Dr. Birendra Pramanik’s group and Dr. Tse-Ming Chan’s group
for analytical support, and Dr. Jesse Wong, Dr. Xian Liang,
and Yan Jin for scale-up of some key intermediates. We also
thank Robert Budich for the nomenclature of all the compounds.
tetracycles. Therefore, we switched our attention to nonaromatic
six-membered ring systems as exemplified by 23a-i. Initially,
morpholine analogue 23a was found to be a very potent mGluR1
antagonist (IC50 ) 2.2 nM). Further isosteric replacement of
4-Me of the right-hand phenyl ring with 4-Cl and 4-MeO
generated 23c and 23e, with approximately equal potency
against mGlu1 receptors. Anticipating that substituents on the
morpholine ring would attenuate potential metabolism of the
methylene sites and also reduce the π-stacking, we next prepared
four methyl-substituted analogues 23f-i from commercially
available enantiomerically pure amino alcohols. As shown in
Table 1, 3-Me substituted analogues 23h and 23i were more
potent than their 2-Me countparts 23f and 22g, respectively;
for 2-Me and 3-Me substituted series, the R-isomers (23g, 23i)
were 2-fold more potent than their corresponding â-isomers (23f,
23h). We also examined two 3(R)-Me substituted analogues 23b
and 23d, both of which showed single-digit nanomolar human
mGluR1 potency. It is noteworthy that most of the morpholine
analogues exhibited subnanomolar Ki values against rat mGlu1
receptors. As shown in Table 1, all the tetracycles demonstrated
high selectivity against human mGlu5 receptors.
Note Added after ASAP Publication. This manuscript was
released ASAP on October 11, 2007 with errors in Table 1.
The correct version was posted on October 16, 2007.
Supporting Information Available: Experimental procedures.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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JM070590C