Rational design, synthesis, and structure-activity relationship of benzoxazolones: New potent mglu5 receptor antagonists based on the fenobam structure

Article abstract of DOI:10.1016/j.bmcl.2006.12.006

A novel class of potent and stable mGlu5 receptor antagonists was developed by combining information from a high-throughput screening campaign with the structure of the known anxiolytic fenobam. Representative compounds from this class show favorable phar

Full text of DOI:10.1016/j.bmcl.2006.12.006

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1302–1306
Rational design, synthesis, and structure–activity relationship of
benzoxazolones: New potent mglu5 receptor antagonists
based on the fenobam structure
Simona M. Ceccarelli,a,* Georg Jaeschke,a Bernd Buettelmann,a Jorg Huwyler,b
¨
Sabine Kolczewski,a Jens-Uwe Peters,a Eric Prinssen,a Richard Porter,a
Will Spoorena and Eric Vieiraa
aPharmaceutical Division, Discovery Research, F. Hoffmann-La Roche Ltd,CH-4070 Basel, Switzerland
bUniversity of Applied Sciences, Northwestern Switzerland Institute for Pharma Technology,
Gru¨ndenstrasse 40, CH-4132 Muttenz, Switzerland
Received 17 October 2006; revised 1 December 2006; accepted 3 December 2006
Available online 15 December 2006
Abstract—A novel class of potent and stable mGlu5 receptor antagonists was developed by combining information from a high-
throughput screening campaign with the structure of the known anxiolytic fenobam. Representative compounds from this class
show favorable pharmacokinetic properties and are active in an in vivo model of anxiety.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The metabotropic glutamate receptors (mGlus) are a
class of G-protein coupled receptors which respond to
the excitatory neurotransmitter glutamate.1 Eight sub-
types of mGlus have been identified, which are divided
into several subclasses based on sequence similarity, sec-
ond messenger coupling, and pharmacology.2 The
mGlu5 receptor belongs to group I mGlus and upon
binding of glutamate activates phospholipase C, result-
ing in the mobilization of intracellular calcium. It has
been shown that selective modulation of mGlu5 is useful
in the treatment of various pain states3 and pre-clinical
evidence supports the use of mGlu5 antagonists in the
treatment of mood disorders, in particular anxiety and
depression.4 Additional evidence suggests the potential
utility of mGlu5 modulation in the treatment of a wide
range of psychiatric and neurological disorders, includ-
ing schizophrenia, Parkinson’s disease, cognitive dys-
function, epilepsy, and drug addiction.5 mGlu5
possesses a unique allosteric site in the transmembrane
region, which makes it a particularly attractive target
for pharmacological modulation, since it allows for
selectivity against other mGlus.4
The limitations of currently available anxiolytics sup-
port a continuing interest in novel targets for the treat-
ment of anxiety states. In this respect, the mGlu5
receptor appears to be an attractive target, due to the
validated proof of concept6 and the potential for selec-
tivity and chemical tractability offered by the allosteric
site. The attention of the pharmaceutical industry for
this target is testified by the growing body of patents7
and scientific literature8 detailing the development of
allosteric mGlu5 modulators. Among these, MPEP (1)
and MTEP (2) constitute the most advanced and docu-
mented non-competitive mGlu5 receptor antagonists
and have reached the status of prototypical pharmaco-
logical tools for this target.9
S
N
N
N
1, MPEP
2, MTEP
Porter et al. recently reported the finding that fenobam
3, a clinically tested anxiolytic agent developed by
McNeil more than 30 years ago,10 is also a non-compet-
itive mGlu5 antagonist,11 showing in our hands a
Keywords: mGluR5; Fenobam; Anxiety; MPEP; Benzoxazolone.
*
Corresponding author. Tel.: +41 0 61 6884437; fax: +41 0 61
6886459; e-mail: Simona_m.ceccarelli@roche.com
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.12.006

S. M. Ceccarelli et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1302–1306
1303
binding Ki of 61 nM12 and a functional IC50 of 38 nM.13
Fenobam is reported to have extensive in vivo metabo-
lism,14 possibly leading to the poor efficacy and high
variability in exposure observed in clinical studies.10 At-
tempts to identify more stable fenobam analogs were
In the following, SAR, properties, and efficacy in an
in vivo anxiety model of this new class of mGlu5 recep-
tor antagonists will be presented.
Synthesis of the compounds described in this communi-
cation and of related analogs was performed by simple
amide coupling between various anilines I and arylben-
zoic acids II according to standard methodology
(Scheme 1). The functionalized arylbenzoic acids were
either commercially available or synthesized as illustrat-
ed in Scheme 1.
faced with the unyielding structure–activity relationship
´
˚
of related creatinine ureas, as reported by Wallberg
et al.15 and confirmed by our own efforts.16
Creatinine ureas like fenobam 3 exist mainly in the tau-
tomer form B (Fig. 1), stabilized by an intramolecular
hydrogen bond.16 Upon screening of our compound col-
lection aiming at the identification of novel mGlu5 allo-
steric inhibitors, we identified salicylamides such as 4,
showing a binding Ki at the MPEP site comparable to
fenobam. The intramolecular hydrogen bond which is
also a characteristic of the salicylamides led to the
hypothesis that this structural feature could be a key
pharmacophoric element for mGlu5 antagonism.17
Other hit compounds, like quinazoline 5, which can be
seen as an analog of 4 where the H-bond is substituted
by a permanent covalent bond, seemed to further sup-
port this notion. While neither salicylamides nor quina-
zolines were considered promising starting points, the
observation that the carbonyl group in the fenobam
structure and the phenol ring in the salicylic amides
occupy different and complementary positions with re-
spect to the amide bond led to the design of structure
6, combining both elements in a single compact mole-
cule (Fig. 1) which, despite its structural simplicity,
had not been described before. Gratifyingly, already
the first examples synthesized, benzoxazolones 6 and 7,
showed a binding affinity and potency comparable to
fenobam (Fig. 1 and Table 1). The chlorine in position
3 of the phenyl ring, as present in the hit salicylamide
4, did not show any noticeable influence on potency.
2-Oxo-2,3-dihydro-benzooxazole-4-carboxylic acid 10
was synthesized from the corresponding open amino-
O
O
a
+
ArNH2
R
R
OH
N
H
Ar
I
II
III
b
c,d
HO
HO
O
HO
O
O
O
OH
OH
N
O
O
NH2
O
9
NH2
H
e,f
8
10
O
O
HN
11
O
O
O
+ O
g
h
N
O
NH2
NH
O
NH
NH
N
O
O
O
12
13
14
O
O
O
i
j
O
k
HO
HO
H
N
H
N
H
N
N
N
O
NH
O
N
N
N
N
O
N
N
O
O
H
O
H
O
B
N
O
N
O
H
17
18
16
15
O
O
Cl
Cl
A
3, Fenobam
X
Ki: 70 nM
l
m
n
O
O
HO
HO
Cl
O
H
N
N
N
H
N
O
O
O
O
O
H
H
H
N
O
O
O
N
N
O
Cl
19
21
20
H
Cl
O
O
H
6, X = H Ki: 68 nM
7, X = Cl Ki: 95 nM
Cl
4
N
Ki: 70 nM
N
N
H
O
22
N
N
H
I
Scheme 1. Synthesis of the non-commercial arylbenzoic acid used to
generate the compounds described in this paper. Reagents and
conditions: (a) coupling agent (EDC/HBTO, TBTU or CDI), base
(DIPEA, pyridine, TEA or no base), DMF, rt; (b) MeOH, H2SO4,
reflux, 1.5 h; (c) COCl2 20% in toluene, Py, rt, 20 h; (d) NaOH 0.5 N,
rt, 4 h; (e) ClCH2COCl, BnEt3NCl, NaHCO3, CHCl3, 55 ꢁC, 5 h; (f)
NaOH 0.5 N, rt, 4 h; (g) Pd/C, H2, EtOH, rt, 4 h; (h) COCl2 20% in
toluene, Py, rt, 20 h; (i) NaOH 1 N, rt, 4 h; (j) MeI, K2CO3, CH3CN,
50 ꢁC, 2 h; (k) NaOH 1 N, rt 4 h; (l) i. H2, Pd/C, EtOH; ii. H2, Pd/C,
EtOH, HCl; (m) NaOH, MeOH; (n) KMnO4, KOH/H2O, 100 ꢁC,
24 h.
H
N
N
N
Cl
5
Ki: 116 nM
Figure 1. Comparison between the most stable tautomeric form of
fenobam 3, the salicylamide 4, the quinazoline 5, and the benzoxazol-
ones 6 and 7, highlighting the elements which have been combined to
generate the new structures.

1304
S. M. Ceccarelli et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1302–1306
Table 1. Binding constants of analogs of compound 6 where the
benzoxazolone is replaced by other benzocondensed heterocycles
ing from the 2-acetylamino-3-nitro-benzoic acid methyl
ester 12 through reduction of the nitro group and cycli-
zation to the monoprotected urea 14 with phosgene, fol-
lowed by deprotection and hydrolysis. The protected
intermediate 14 can also be monomethylated to prepare
the methylated analog 17. Lactame 20, where the oxygen
of the benzoxazolone is substituted by a methylene
group, was prepared from the commercially available
dioxoindoline 18 via selective reduction and hydrolysis.
Benzotriazole 22 was prepared from the corresponding
7-methyl benzotriazole 21 by oxidation of the methyl
group with potassium permanganate.
H
N
R
O
Cl
Compound
R
Ki (nM)
6
68a
O
N
H
O
Table 1 illustrates binding constants of analogs of com-
pound 6 where the benzoxazolone is replaced by other
ring systems. The hypothesis that an intramolecular
hydrogen bond involving the amide carbonyl is a key
element for mGlu5 inhibition in this series is supported
by the fact that the inverted benzoxazolone isomer 23
shows no binding affinity. The indolinone 24, despite
being a closer analog to the fenobam creatinine ring,
shows a reduced Ki. This is also the case for the homolog
25 of benzoxazolone 6, having a six-membered oxazi-
none ring. The open-chain analog 26, surprisingly, is
completely inactive. Other H-bond forming heterocyclic
analogs, like the benzimidazolinones 27 and 28, and the
aromatic systems 29–31 show a very reduced or no bind-
ing affinity at all.
23
24
>10000
397
NH
O
O
N
H
O
O
25
2900
HN
O
26
27
28
29
30
31
>10000
3900
On the aniline side (Table 2), the analogy between the
SAR of the benzoxazolones and that of the MPEP-
type compounds and fenobam was soon apparent.16
As observed for several classes of mGlu5 allosteric
inhibitors, a single spherical lipophilic substituent in
the meta position brings the highest binding affinity
and functional activity, as shown in Table 2 (com-
pounds 33–37). The simple unsubstituted phenyl, as
in 32, as well as compounds with ortho or para substi-
tution and doubly substituted compounds (examples
38–40, Table 2) show a substantially reduced binding
affinity. In Table 2 are also shown binding affinities
of a few selected heteroarylamine derivatives. Also in
this set, analogies to the known SAR of other classes
of mGlu5 receptor antagonists are found, with the
MPEP substituent 6-methylpyridin-2-yl (42) showing
the highest affinity and functional activity. The
MTEP-type substituent 2-methyl-1,3-thiazol-5-yl (43),
as well as the 2-pyridyl derivative 41, retain a binding
affinity of 0.25 lM. Other heterocyclic amide deriva-
tives, as for example, 44 and 45, show much reduced
affinity. Any attempt to substitute the amide NH with
small alkyl chains led to completely inactive com-
pounds (unreported data).
N
H
O
NH
O
N
H
>10000
3900
N
O
N
H
N
H
>10000
>10000
N
N
N
H
N
H
N
In view of its high functional activity, reasonable solu-
bility (30 mg/L),18 and good foreseen permeation behav-
ior (PAMPA Pe: 7.13 cm/s · 10À6),19 compound 42 was
selected for in vivo characterization. Single dose rat
pharmacokinetics showed, contrary to what was report-
ed for fenobam,14 a very promising profile, with a clear-
ance of 8.2 ml/min/kg and an oral bioavailability of
64%. Volume of distribution was very low (0.18 L/kg),
leading to a relatively short half-life (0.22 h). A prelimin-
a Functional assay: Ca2+ efflux IC50 (FLIPR): 195 nM.
phenol 9 via cyclization with phosgene followed by ester
hydrolysis. From the same aminophenol 9, the six-mem-
bered ring analog 11 could be accessed by treatment
with chloroacetyl chloride and sodium hydrogencarbon-
ate in the presence of a phase transfer catalyst. Synthesis
of the cyclic urea derivative 15 was accomplished start-

S. M. Ceccarelli et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1302–1306
Table 2. SAR of benzoxazolone derivatives at the aniline site
1305
0.8
0.6
0.4
0.2
0.0
-0.2
H
N
R
O
O
N
H
*
O
Compound
R
Ki (nM)
6
3-Cl–Ph
Ph
68
***
32
33
34
35
36
37
38
39
40
2200
56a
3-Br–Ph
3-CN–Ph
3-CF3–Ph
3-CH3–Ph
3-MeO–Ph
2-Cl–Ph
4-Cl–Ph
3,5-Cl2–Ph
327
Veh
10
Dose (mg/Kg po)
30
485
109b
3900
>10000
3800
>10000
Figure 2. Effect of compound 42 on DT in the stress induced
hyperthermia (SIH) model of anxiety in NMRI mice.4a Vehicle: 0.3%
Tween 80 in 0.9% NaCl. Pre-treatment time: 60 min. Statistics:
*p < 0:05 compared to vehicle with a T-test independent by group;
***p < 0:001 compared to vehicle with a T-test independent by group.
N
N
N
41
42
43
44
45
251
benzoxazolone class an attractive option for the devel-
opment of anxiolytics targeting mGlu5. Intramolecular
hydrogen bonding, moreover, could be used as a leading
concept for the rational design of novel and diverse
mGlu5 allosteric inhibitors.
95c
250
S
N
Acknowledgments
1970
3100
N
N
Grateful thanks are expressed to Patrick Boissin, Mari-
anne Ruher, Daniel Rueher, and Antonio Ricci for their
excellent technical assistance.
a Functional assay: Ca2+ efflux IC50 (FLIPR): 94 nM.
b Functional assay: Ca2+ efflux IC50 (FLIPR): 104 nM.
c Functional assay: Ca2+ Efflux IC50 (FLIPR): 60 nM.
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fenobam is a mGlu5 allosteric inhibitor and comparison
of its structure with that of salicylamide 4 (which was
found as a hit after screening our compound library
for mGlu5 binders at the allosteric site) led to the
hypothesis that an intramolecular hydrogen bond might
be a pharmacophoric feature of this type of mGlu5 allo-
steric inhibitors. Based on this concept, compound 6 was
designed combining features of fenobam 3 and salicyl-
amide 4. Despite the limited options for structural
variation, SAR exploration led to 2-oxo-2,3-dihydro-
benzooxazole-4-carboxylic acid (6-methyl-pyridin-2-yl)-
amide 42, which showed good pharmacokinetic proper-
ties and efficacy in an in vivo model of anxiety. The
small size and promising profile of 42 make the

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¨
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