Discovery of novel heteroarylazoles that are metabotropic glutamate subtype 5 receptor antagonists with anxiolytic activity

Article abstract of DOI:10.1021/jm049828c

The highly potent, selective, and brain-penetrant metabotropic glutamate subtype 5 (mGlu5) receptor antagonists 3-(5-pyridin-2-yl-2H-tetrazol-2-yl) benzonitrile (47) and 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (48) are reported. Compound 47 is active in the rat fear-potentiated startle (FPS) model of anxiety with ED₅₀ = 5.4 mg/kg (po) when dosed acutely. In this model the anxiolytic effects of 47 rapidly tolerate on repeated dosing.

Full text of DOI:10.1021/jm049828c

J . Med. Chem. 2004, 47, 4645-4648
4645
Sch em e 1a
Discover y of Novel Heter oa r yla zoles Th a t
Ar e Meta botr op ic Glu ta m a te Su btyp e 5
Recep tor An ta gon ists w ith An xiolytic
Activity
J effrey Roppe,† Nicholas D. Smith,† Dehua Huang,
Lida Tehrani, Bowei Wang, J effrey Anderson,
J esse Brodkin, J anice Chung, Xiaohui J iang,
Christopher King, Benito Munoz, Mark A. Varney,
Petpiboon Prasit, and Nicholas D. P. Cosford*
Merck Research Laboratories, 3535 General Atomics Court,
San Diego, California 92121
Received March 1, 2004
Abstr a ct: The highly potent, selective, and brain-penetrant
metabotropic glutamate subtype 5 (mGlu5) receptor antago-
nists 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (47) and
3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (48) are
reported. Compound 47 is active in the rat fear-potentiated
startle (FPS) model of anxiety with ED50 ) 5.4 mg/kg (po) when
dosed acutely. In this model the anxiolytic effects of 47 rapidly
tolerate on repeated dosing.
a
Reagents and conditions: (a) TMSBr, DMSO, MeCN, 0-25
°C, 3 h; (b) 3-cyanophenylboronic acid, Pd(PPh3)4, K2CO3, DME,
H2O, 84 °C, 18 h, two steps 14%; (c) 2-bromo(pyridin-2-yl)zinc,
Pd(PPh3)4, PPh3, THF, 70 °C, 5 h, 9%; (d) TBAF, THF, 10 min,
80%; (e) 3-fluorobenzonitrile, K2CO3, DMF, 145 °C, 14 h, 37%; (f)
(i) ethylvinyl ether, (COCl)2, 0 °C, 12 h; (ii) NEt3, THF, 5 h, ∆; (g)
(i) concentrated HCl, 25 °C, 3 h, 45%; (ii) (CF3SO2)O, THF, -78
to 25 °C, 4 h, 80%; (h) 3-cyanophenylboronic acid, Pd(PPh3)4,
K2CO3, DME, H2O, 65 °C, 12 h, 39%; (i) 3-fluorobenzonitrile,
K2CO3, DMF, 145 °C, 18 h, 38%.
Excessive activation of G-protein-coupled metabotro-
pic glutamate subtype-5 (mGlu5) receptors in the cen-
tral nervous system, leading to aberrant glutamatergic
neurotransmission, has been implicated in a number of
disease states.1,2 Selective mGlu5 receptor antagonists,
therefore, may be of therapeutic benefit in the treatment
of pain,3 anxiety and depression,4-6 drug dependence,7
or mental retardation.8 We have recently reported the
design and synthesis of the potent and selective non-
competitive mGlu5 receptor antagonists 3-[(2-methyl-
1,3-thiazol-4-yl)ethynyl]pyridine (1a ),9 an analogue of
the prototypical mGlu5 receptor antagonist 2-methyl-
6-(phenylethynyl)pyridine (1b) with anxiolytic activity,
and 2-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]aceto-
nitrile (2)10 from a different structural series.
trile 3. Compound 3 inhibited mGlu5 receptors in vitro
(vide infra) in a functional assay (Ca2+ flux IC50 ) 0.05
µM) and a binding assay (Ki ) 0.21 µM), and these
results led us to speculate that the oxazole in 3 might
be a surrogate for the ethyne moiety in 1a and 1b.
During these investigations, a series of heteroarylpyri-
dine mGlu5 receptor antagonists, including the oxadia-
zole derivative 4a , with a clear structural resemblance
to 3 were disclosed in a patent application.11 The
compounds described in this patent application con-
tained five-membered heteroaryl moieties linking py-
ridine and phenyl via ring carbon atoms of the heteroar-
yl linker. It was apparent, however, that an almost
identical pharmacophore would result from structures
in which one of the carbon attachment atoms was
replaced with a nitrogen atom. For analogues containing
one phenyl and one 2-pyridyl unit there are 16 possible
five-membered ring derivatives containing isomers of
pyrrole, pyrazole, imidazole, triazole, or tetrazole, as in
structure 4b. The synthesis of each of the 16 “N-linked”
analogues of 4a (i.e., 2-pyridyl/linker/3-cyanophenyl)
was therefore undertaken in order to assess the relative
in vitro potency of each compound compared with 4a .
During structure-activity relationship (SAR) studies
focused on defining the common structural features of
1a , 1b, and 2, the benzoxazole unit in 2 was replaced
with a 2-(1,3-oxazol-4-yl)pyridine moiety to give [2-meth-
oxy-4-(4-pyridin-2-yl-1,3-oxazol-2-yl)phenyl]acetoni-
The chemical synthesis of the N-linked azole ana-
logues is summarized in Schemes 1-3 (detailed proce-
dures may be found in the Supporting Information).
Yields reported are unoptimized. The nature of the
structures required that a different preparative se-
quence had to be developed for each unique hetero-
cyclic scaffold to provide the desired target compounds.
* To whom correspondence should be addressed. Phone: 858-202-
5299. Fax: 858-202-5752. E-mail: nicholas_cosford@merck.com.
† These authors contributed equally to the work described in this
manuscript.
10.1021/jm049828c CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/14/2004

4646 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 19
Letters
Sch em e 2a
Sch em e 3a
a
Reagents and conditions: (a) TMSN3, 95 °C, 18 h, 25%; (b)
3-fluorobenzonitrile, K2CO3, DMF, 140 °C, 18 h, 13% (34) and 29%
(35); (c) concentrated HBr, 8 h, ∆, 80%; (d) N-fluoropyridinium
triflate, NaOMe, MeOH, -78 to 25 °C, 16 h, 20%; (e) 3-cyanophe-
nylboronic acid, Pd(PPh3)4, K2CO3, PhMe, MeOH, 90 °C, 16 h, 54%;
(f) (i) NH2NH2, EtOH, 25 °C, 18 h, 57%; (ii) HCO2H, 0-25 °C,
then ∆, 4 h, 38%; (g) 3-fluorobenzonitrile, K2CO3, DMF, 145 °C,
16 h, 60%; (h) TMSN3, Bu2SnO, PhMe, 110 °C, 1 h, 34%; (i)
N-fluoropyridinium triflate, NaOMe, MeOH, -78 to 25 °C, 3 h,
31%; (j) (i) CH3C6H4SO2NHNH2, EtOH, 25 °C, 0.5 h; (ii) NaOH,
25 to -5 °C; (iii) HCl (6 M), NaNO2, H2O, 3-aminobenzonitrile (R
) H) or 3-amino-5-fluorobenzonitrile (R ) F), -5 °C, 55% (47),
80% (48).
a
Reagents and conditions: (a) (MeO)2CHCH2CH(OMe)2, HCl,
EtOH, 75 °C, 2 h; (b) Br2, AcOH, 25 °C, 3 h, two steps 82%; (c)
3-cyanophenylboronic acid, Pd(PPh3)4, K2CO3, DME, H2O, 70 °C,
14 h, 12%; (d) NH2NH2, EtOH, 75 °C, 18 h, 86%; (e) 3-cyanophe-
nylboronic acid, Cu(OAc)2, pyridine, CH2Cl2, 25 °C, 48 h, 8%; (f)
4-bromo-1H-imidazole, NMP, 165 °C, 18 h, 44%; (g) 3-cyanophe-
nylboronic acid, Pd(PPh3)4, K2CO3, DME, H2O, 80 °C, 18 h, 4%;
(h) 3-fluorobenzonitrile, K2CO3, DMF, 145 °C, 18 h, 38%; (i) (i)
MeNO2, HNEt2, THF, 55 °C, 48 h, 77%; (ii) MeSO2Cl, NEt3,
CH2Cl2, 0-25 °C, 93%; (iii) TMSN3, TBAF, DMF, 50 °C, 20 min,
81%; (j) N-fluoropyridinium triflate, NaOMe, MeOH, -78 to 25
°C, 18 h, 20% (30) and 17% (31).
Worthy of note is the SNAr substitution protocols
employed to synthesize pyrrole 10, pyrazole 16, imida-
zole 27, and triazoles 34, 35, and 42; a C-N cross-
coupling procedure to prepare pyrazole 22;12 and the use
of N-fluoropyridinium triflate to construct triazoles 30
and 31 and tetrazole 45.13 We have recently described
an alternative procedure for the synthesis of pyrrole
derivatives such as 6.14
Each of the N-linked azole analogues, synthesized as
described in Schemes 1-3, was initially profiled in two
in vitro assays. Functional potency was assessed using
an automated assay employing Ltk cells stably express-
ing human recombinant mGlu5 receptors.15 This cell-
based assay measures changes in cytosolic Ca2+ con-
centrations ([Ca2+]i) by fluorescence detection using the
Ca2+-sensitive dye fura-2. Binding to native mGlu5
receptors in vitro was determined by measuring the
displacement by test compounds of [3H]-3-methoxy-5-
(pyridin-2-ylethynyl)pyridine (1c) from rat cortical mem-
branes.16 The results of the in vitro profiling of the new
compounds are presented in Table 1.
N-linked to pyridyl 7 was a very weak antagonist in both
assays while its isomer 10 is relatively potent in the
Ca2+ flux assay. Of the four pyrazole isomers, only 16
(Ca2+ flux IC50 ) 0.44 µM; Ki ) 0.53 µM) and 22 (Ca2+
flux IC50 ) 0.14 µM; Ki ) 0.25 µM), which are both
N-linked to phenyl, showed comparable potency with
4a . Interestingly, both of the imidazole isomers11 (25
and 27) are very weak antagonists. In the 1,2,3-triazole
series the isomers linked at 1-N (30 and 34) and the
1,2,4-triazole isomers (39 and 42) show very weak
activity.
By comparison, the 1,2,3-triazole isomers linked at
2-N, i.e., 31 (Ca2+ flux IC50 ) 0.21 µM; Ki ) 0.20 µM)
and 35 (Ca2+ flux IC50 ) 0.08 µM; Ki ) 0.30 µM) both
show reasonable potency. Finally, the tetrazole N-linked
to pyridyl (45) shows moderate potency (Ca2+ flux IC50
) 0.27 µM; Ki ) 0.45 µM) while the isomer that is
N-linked to phenyl (47) proved to be more potent in vitro
than 4a (Ca2+ flux IC50 ) 0.07 µM; Ki ) 0.19 µM). On
the basis of the in vitro data, 10, 22, 31, 35, and 47 were
selected for further evaluation. The pharmacokinetic
properties of each compound were measured in rats, and
the data are displayed in Table 2. While pyrazole 22
exhibited a promising half-life in rats (t1/2 ) 5.5 h),
neither 10, 22, nor 35 showed any appreciable oral
bioavailability. Compound 31 exhibited an oral bioavail-
ability in rats of 13% although the half-life was rela-
Oxadiazole 4a , which was evaluated for comparison,
exhibited good potency in the Ca2+ flux assay (IC50
)
0.10 µM) and modest binding potency (Ki ) 0.49 µM).
Considering the relatively minor structural differences
between the 16 N-linked azole analogues, there is wide
variation in potency in vitro. For example, the pyrrole

Letters
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 19 4647
Ta ble 1. In Vitro Potency Data for mGlu5 Receptor
Ta ble 3. In Vivo Data for mGlu5 Receptor Antagonists 47 and
Antagonistsa
48a
Occ ED50
Occ ED50 plasma levels brain levels FPS ED50
(mg/kg ip) (mg/kg po)
(µM)
(µM)
(mg/kg po)
47
48
3.0b
1.3b
3.0c
3.6d
10.5 ( 4.5e
2.7 ( 0.9f
15.3 ( 6.0e
2.4 ( 0.1f
5.4g
NT
a
Occ ) in vivo receptor occupancy; FPS ) fear-potentiated
b
startle. Measured 1 h postadministration (n ) 5-6 Sprague-
Dawley rats/group). c Measured 30 min postadministration (n )
d
6-7 Sprague-Dawley rats/group). Measured 2 h postadminis-
tration (n ) 5-7 Sprague-Dawley rats/group). e Measured at 1 h
following 10 mg/kg dose ip. f Measured at 1 h following 3 mg/kg
g
dose ip. Measured 1 h postadministration (n ) 8 Wistar rats/
group).
) 0.004 µM and Ki ) 0.012 µM, is equipotent with 1a
with respect to both functional (Ca2+ flux IC50 ) 0.005
µM) and binding potency (Ki ) 0.016 µM) in vitro.
Furthermore, 48 exhibits promising pharmacokinetics
in rats (t1/2 ) 2.9 h, F ) 26%; Table 2). The impressive
in vitro potency and pharmacokinetic profiles of 47 and
48 led to selection of these compounds for further in
vitro and in vivo evaluation.
To identify any off-target activities, tetrazole 47 was
profiled extensively against a battery of in vitro assays
(MDS Pharma Services screen). Experiments were
performed at a drug concentration of 10 µM; under this
paradigm no significant off-target effects were observed.
As with the alkyne derivative 1a , 47 is highly selective
for the mGlu5 receptor over the mGlu1 receptor (mGlu1
Ca2+ flux IC50 > 10 µM) although the effect of 47 as a
positive or negative modulator of other mGlu receptor
subtypes is yet to be determined. Evaluation of the brain
penetration of 47 and 48 was undertaken using an in
vivo receptor occupancy assay, which has been described
previously, and this allowed correlation of affinity at
mGlu5 receptors with in vivo efficacy.17,18 Briefly, at
time zero rats were dosed with the test compound and
1c16 was administered via tail vein injection at the time
of maximum drug concentration (Tmax). One minute
later the animals were sacrificed and binding of the drug
to brain tissue was measured. By use of this procedure,
dose-response relationships were generated for the
binding of 47 and 48 to mGlu5 receptors in vivo. In
addition, plasma and brain levels for 47 and 48 were
measured (Table 3). Thus, 47 exhibits an occupancy
ED50 of 3 mg/kg when administered either intraperito-
neally or perorally. Compound 48, with an oral bioavail-
ability of 26%, exhibits occupancy ED50 values of 1.3 mg/
kg (ip) and 3.6 mg/kg (po). Both tetrazole derivatives
show good brain penetration and similar brain/plasma
ratios (Table 3).
Several recent studies suggest a role for mGlu5
receptors in the modulation of mood disorders such as
anxiety.4-6 Experiments in this laboratory have dem-
onstrated that 1a blocks fear-conditioning in rats as
determined in the fear-potentiated startle (FPS) model
of anxiety.9 Thus, in the FPS model it was found that
acute administration of 47 perorally in rats blocked the
expression of fear with an ED50 of 5.4 mg/kg. This
finding with 47, a compound derived from a new
structural class, is fully consistent with results in the
FPS model observed with alkyne derivative mGlu5
receptor antagonists such as 1a . To assess the anxiolytic
profile on chronic dosing, rats were tested using the FPS
protocol each day for 5 consecutive days immediately
a
Data are presented as the geometric mean followed in paren-
theses by the lower and upper limits of the mean and the number
of replicates. Ca2+ flux assay using glutamate as agonist.15
b
c Displacement by test compounds of [3H]-3-methoxy-5-(pyridin-
2-ylethynyl)pyridine (1c) bound to rat cortical membranes.16
Ta ble 2. Rat Pharmacokinetic Data for mGlu5 Receptor
Antagonistsa
b
Clp (mL min-1 kg-1
)
Vd (L/kg)b
t1/2 (h)b
F (%)c Cmax (µM)c
10
22
31
35
47
48
32.5 ( 2.0
9.7 ( 1.1
15.1 ( 1.6
15.7 ( 5.6
32.9 ( 2.8
16.9 ( 2.5
3.6 ( 0.7 1.7 ( 0.8
3.7 ( 0.3 5.5 ( 0.3
1.0 ( 0.5 1.7 ( 0.6
1.1 ( 0.5 2.5 ( 0.8
5.0 ( 1.1 6.9 ( 1.0
1.1 ( 0.1 2.9 ( 2.6
4
3
13
3
100
26
0.9 ( 0.2
1.2 ( 0.1
2.7 ( 0.8
0.6 ( 0.3
5.8 ( 0.5
2.5 ( 1.6
a
Clp ) clearance; Vd ) volume of distribution; t1/2 ) half-life; F
b
) biovailability; Cmax ) maximum concentration. 2 mg/kg dosed
iv (n ) 2 Sprague-Dawley rats/group). c 10 mg/kg dosed po (n ) 3
Sprague-Dawley rats/group).
tively short (t1/2 ) 1.7 h). This is in marked comparison
with the tetrazole (47), which is both bioavailable (F )
100%) and has a long half-life in rats (t1/2 ) 6.9 h).
Continued structure-activity optimization studies around
tetrazole 47 led to the observation that fluoro substitu-
tion at the 3-position of the benzonitrile moiety in 47
resulted in a significant enhancement in potency at
mGlu5 receptors. Thus, tetrazole 48, with Ca2+ flux IC50

4648 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 19
Letters
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Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the synthesis of 7-48. This material is available free
of charge via the Internet at http://pubs.acs.org.
J M049828C