Discovery of oxazolobenzimidazoles as positive allosteric modulators for the mGluR2 receptor

Article abstract of DOI:10.1021/ml100115a

Novel oxazolobenzimidazoles are described as potent and selective positive allosteric modulators of the metabotropic glutamate receptor 2. The discovery of this class and optimization of its physical and pharmacokinetic properties led to the identificatio

Full text of DOI:10.1021/ml100115a

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Discovery of Oxazolobenzimidazoles as Positive
Allosteric Modulators for the mGluR2 Receptor
Robert M. Garbaccio,*,† Edward J. Brnardic,† Mark E. Fraley,† George D. Hartman,†
Pete H. Hutson,‡ Julie A. O'Brien,§ Brian C. Magliaro,‡ Jason M. Uslaner, Sarah L. Huszar,
Kerry L. Fillgrove,^ James H. Small,^ Cuyue Tang,^ Yuhsin Kuo,^ and Marlene A. Jacobson‡
Departments of †Medicinal Chemistry, ‡Psychiatry Research, §In Vitro Sciences, Central Pharmacology, and
^Drug Metabolism, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, Pennsylvania 19486
ABSTRACT Novel oxazolobenzimidazoles are described as potent and selective
positive allosteric modulators of the metabotropic glutamate receptor 2. The
discovery of this class and optimization of its physical and pharmacokinetic
properties led to the identification of potent and orally bioavailable compounds
(20 and 21) as advanced leads. Compound 20 (TBPCOB) was shown to have robust
activity in a PCP-induced hyperlocomotion model in rat, an assay responsive to
clinical antipsychotic treatments for schizophrenia.
KEYWORDS Oxazolobenzimidazoles, allosteric modulators, metabotropic gluta-
mate 2 receptor, hyperlocomotion model, schizophrenia, GPCR
chizophreniaisachronic,debilitatingdisorderaffecting
1% of the world population.1-3 Current treatments
target dopamine D2 and serotonin 5-HT2A receptors
group II mGlu receptors, selective mGluR2 agonists have not
been discovered. An alternative approach takes advantage of the
less homologous transmembrane domain of these receptors
where positive allosteric modulators (PAMs) have been shown to
bind selectively to mGluR2.12 In fact, a significant number of
nonamino acid mGluR2-selective PAMs have been reported
in the literature, by both Merck13 and others.14-16 Selective
mGluR2 PAMs have several potential advantages over an orthos-
teric agonist: (1) avoidance of potential mGluR3-mediated
effects, (2) reduced potential for tachyphylaxis, which has been
observed with GPCR agonists upon chronic treatment,17 and (3)
the selective activation of this receptor only in relevant tissues in
the presence of endogenous agonist glutamate.
S
and are effective in treating the positive symptoms of
schizophrenia (hallucinations and delusions) but offer lim-
ited efficacy for the negative symptoms (apathy, anhedonia,
and social withdrawal) and do not improve cognitive deficit
characteristic of this disease.4 In addition, patient use of
some of the currently prescribed antipsychotic agents is
accompanied by undesirable side effects including signi-
ficant weight gain, hyperglycemia, diabetes, sedation, and
various dyskinesias.5 Thus, there is a clear need for improved
therapeutics with novel mechanisms of action.
In this report, the discovery of a novel series of oxazolo-
benzimidazole mGluR2 PAMs is described. Following opti-
mization of physical and pharmacokinetic properties, an
advanced compound was demonstrated to be orally effica-
cious in a rat PCP-induced hyperlocomotion model predic-
tive of antipsychotic potential.
L-Glutamate is the major excitatory neurotransmitter in the
mammalian central nervouse system (CNS), and it is hypothe-
sized that elevated glutamate transmission in the forebrain is
associated with schizophrenia symptomatology. Therefore, a
treatment that could reduce synaptic glutamate levels might be
therapeutically beneficial for treating this disease.6,7 As glutamate
levels are regulated presynaptically by group II mGlu receptors
(mGluR2 and -3) as well as group III (mGluR4, -6, -7, and -8),8
these mGluR's have been identified as potential targets for
novel treatments. Importantly, and in support of this “gluta-
mate hypothesis”, (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicy-
clo[3.1.0]hexane-4,6-dicarboxylic acid (LY2140023, 1), a
nonselective mGluR2/3 agonist prodrug (Figure 1), has de-
monstrated efficacy against both positive and negative symp-
toms in a 4 week phase IIb study in schizophrenia patients.9
Evidence from behavioral studies in mGluR2 and mGluR3 KO
mice suggest that the antipsychotic activity of the mGluR2/3
agonist is derived from the activation of mGluR2;10,11 however,
because of a high degree of homology in the orthosteric sites of
In a previous publication,18 the HTS hit to lead optimiza-
tion for an oxazolidinone series of mGluR2 PAMs was
described and culminated in the identification of tert-butyl-
phenoxymethyl oxazolidinone 2. Despite significant effort,
further optimization of potency and pharmacokinetic
properties proved elusive within this architecture. An im-
portant observation from the oxazolidinones structure-
-activity relationship (SAR) was that ortho substitution on
the N-aryl ring was not tolerated, suggesting a preference for
Received Date: May 14, 2010
Accepted Date: June 30, 2010
Published on Web Date: July 12, 2010
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Figure 1. Dual mGluR2/3 agonist and prodrug.
Figure 3. Comparison of properties between 2 and 3.
oxazolidinone 2 even without the previously identified po-
tency-enhancing CN group present (Figure 3).18
Despite this initial success in potencyoptimization and the
discovery of a novel mGluR2 PAM scaffold, oxazolobenzimi-
dazole 3 possessed poor physical properties as highlighted
by high logD and negligible aqueous solubility. Pharmaco-
kinetic experiments in dog and rat further indicated that
oxazolobenzimidazole 3 was a high clearance compound
with a short half-life and poor microsomal stability. Given
these challenges, further optimization was required to ren-
der this second generation series “druglike”, orally bioavail-
able, and amenable to in vivo efficacy studies.
Figure 2. Proposed constraint of oxazolidinone lead to oxazolo-
benzimidazole.
Scheme 1. Synthesis of 3a
In addition to our desire to lower logD and improve aqueous
solubility, we set out to identify and impede sites of oxidative
metabolism as an added strategy to improve pharmacokinetics.
Using human liver microsomes and liquid chromatography-
mass spectrometry analysis, primary metabolites were identi-
fied for 3 and indicated extensive oxidation on both ends of the
molecule. Specifically, oxidation of both the tert-butyl group and
the benzimidazole were prevalent. As a direct result of these
observations, polar, electron-withdrawing substituents were
envisioned at both ends of the molecule to simultaneously
improve logD and solubility and to block metabolism.
An alternative synthetic route was devised that enabled the
coupling of modified tert-butylphenols to a late stage oxazolo-
benzimidazole intermediate. Among the numerous phenols
incorporated in this series, 11 and 16 proved to be uniquely
valuable, and their synthesis is described below (Scheme 2).
2-Bromo-5-(trisiopropylsilyloxy)pyridine (8, R = TIPS) was re-
acted with an excess of copper(I) cyanide and the tert-butyl
Grignard reagent to directly install the tert-butyl group in modest
yield.21 Subsequent deprotection of the silyl ether 10 using
tetrabutylammonium fluoride provided 2-tert-butyl-5-hydroxy-
pyridine 11 in good yield. Alternatively, the analogous bromide 9
(R = Me) underwent metal halogen exchange and trap with
dimethylacetamide to yield ketone 12. Trifluoromethane anion
addition to 12 and mesylation provided intermediate 14 in low
yield but on a large scale. Mesylate 14 was then reacted with
trimethylaluminum to form the quaternary center in pyridyl-
ether 15.22 Sodium ethane thiolate in dimethyl formamide
(DMF) at elevated temperature was utilized to provide the
pyridyl phenol 16 in good yield.
a Reagents and conditions: (a) NaOH, H2O, 64 ꢀC, 47%. (b) Cs2CO3;
EtOH, 23 ꢀC, 54%.
coplanarity between the oxazolidinone and the aryl ring. In
this second generation approach, a central ring constraint
was envisioned (Figure 2), leading to a proposed oxazolo-
benzimidazole core 3. It was postulated that the enforced
coplanar disposition of the rings in this tricycle would mimic
the bioactiveconformation of 2 and further improve physical
and pharmacokinetic properties in this series with its en-
hanced basicity and reduced rotatable bonds.19
A versatile and efficient chemical route to these oxazoloben-
zimidazoles was developed following literature precedent
(Scheme 1). Alkylation of 4-tert-butyl phenol with (R)-epichlor-
ohydrin provided the (S)-glycidyl phenyl ether 6 due to direct
attack by the phenol on the epoxide carbon and not the one
bearing the chloride, followed by subsequent ring closure to
reform the terminal epoxide. Combination of 6 with 2-chloro-
benzimidazole in the presence of base and heatdirectlyafforded
the desired oxazolobenzimidazole20 3 in moderate yield.
Compounds were evaluated in a Chinese hamster ovary
(CHO) cell line coexpressing recombinant human mGluR2
and a promiscuous G-protein, GR16, using a fluorescent
imaging plate reader (FLIPR) assay. Functional potency
was expressed as the EC50 for potentiating a submaximal
concentration of glutamate (EC20). In this assay, the newly
synthesized oxazolobenzimidazole corewas found to exhibit
a 7-fold more potent EC50 than the corresponding leading
These phenols were appended to the oxazolobenzimid-
azole core (Scheme 3). Relying on extensive SAR established
in the oxazolidinone-based PAMs,18 the inclusion of a nitrile
group into the oxazolobenzimidazole was predicted to
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Scheme 2. Synthesis of Phenols 11 and 14a
a Reagents and conditions: (a) t-BuMgCl, CuCN, THF, -78 to 23 ꢀC.
(b) TBAF, THF, 27%. (c) n-BuLi, dimethylacetamide, -40 to 23 ꢀC, 20%.
(d) CF3SiMe3, LiOAc, DMF, 86%. (e) NaH, DMF then MsCl, 94%.
(f ) Me3Al, CH2Cl2, 0 to 23 ꢀC, 37%. (g) NaSEt, DMF, 150 ꢀC, 64%.
Figure 4. In vitro properties for oxazolobenzimidazoles 20 and 21.
hydrophobic shielding effect to allow for the polar pyridine
nitrogen without further loss in potency. These two groups
proved symbiotic as will later be shown. The trifluoromethyl
group was a neutral substitution for methyl in FLIPR potency,
but its impact was further recognized in subsequent assays.
Modest agonism was observed for 20 (EC50 = 700 nM) and
21 (EC50 = 730 nM); however, the percent activation relative
to a maximum response to glutamate was <30% for both
optimized oxazolobenzimidazoles. The cooperativity of these
leads to shift glutamate potency was measured in FLIPR. This
“left shift” of gluatmate's potency in FLIPR was reported as a
fold shift, and a 1μM concentration ofoxazolobenzimidazoles
20 and 21 produced an increase in the EC50 of glutamate by
9- and 14-fold, respectively.
Scheme 3. Synthesis of Oxazolobenzimidazoles 20 and 21a
The standard assays to measure physical properties were
also employed, and in comparison to the leading oxazolo-
benzimidazole 3, these optimized PAMs showed significantly
improved measured log D values and aqueous solubility. One
potential limitation in this series was the consistent observa-
tion of high plasma protein binding, which may limit the
available free drug in the brain upon dosing. While P-gp
susceptibility was not observed for most members of this
structural class, it was confirmed that neither of these struc-
tures were P-gp substrates for rat or human.
On the basis of these in vitro assays, oxazolobenzimida-
zoles 20 and 21 are among the more potent mGluR2 PAMs
published in the literature. Additionally, with the strategic
installation of the nitrile and pyridine nitrogen, this series
gained druglike physical properties while retaining potential
for CNS penetration. These alterations led to an improve-
ment in pharmacokinetic properties.
Oxazolobenzimidazoles 20 and 21 were dosed as
single compounds to both rat and dog in standard IV/PO
dosing protocols (Table 1). The installation of the polar,
electron-withdrawing groups into leading compound 3 pro-
duced improvements in clearance, the area under the curve
(AUC), and oral bioavailability.
When compared to the parent compound 3, oxazoloben-
zimidazoles 20 and 21 had improved clearance and AUC in
iv-dosed experiments. These reduced clearances, along with
a Reagents and conditions: (a) Cs2CO3, DMSO, 130 ꢀC. (b) Separation of
CN regioisomers, 36% desired isomer. (c) Et3N-3HF, MeCN, 37 ꢀC, 73%.
(d) PS-PPh3, DIAD, CH2Cl2, 65-85%.
improve metabolic stability and potency. Thus, silyl-pro-
tected glycidol (17) was heated with 2-chloro-5-cyanobenzi-
midazole (18) in the presence of cesium carbonate under
microwave irradiation to give the desired oxazolobenzimid-
azole as a mixture of nitrile regioisomers. This mixture of
regioisomers required separation prior to silyl deprotection
affording the oxazolobenzimazole alcohol 19 in high yield.
Mitsunobu etherification with phenols 11 and 16 gave the
desired oxazolobenzimidazoles 20 and 21, and this route
proved amenable to multigram synthesis.
The FLIPR EC50 values of glutamate potentiation were
measured for 20 and 21 and were found to be 29 and 33 nM,
respectively (Figure 4). It is important to note that these
structural series are selective potentiators of mGluR2 and do
not show activity (PAM, agonist, and antagonist) against
other mGlu receptors (mGluRs 1, 3, 4, 5, and 6). On the basis
of the synthesis of other analogues, the general SAR estab-
lished that incorporation of the pyridyl nitrogen caused a 10-
fold loss in potency as measured by FLIPR, and this was
balanced by a 3-fold potency enhancement brought by the
nitrile group. Polarity was generally not tolerated around the
phenol, and the bulky tert-butyl group likely provided a
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Table 1. Pharmacokinetic Properties of Oxazolobenzimidazoles 3, 18, and 19
clearance
volume
compd
species
dose (mpk)
route
vehicle
DMSO
n
half-life (h)
AUC (μM h)
(mL/min/kg)
oral F (%)
distribution (L/kg)
3
3
dog
rat
0.5
2
iv
2
2
2
2
2
2
2
2
2
2
2.1
1.5
1.7
0.78
1.02
14.8
9.48
3.64
27.2
2.38
3.64
9.11
27.3
45.9
103
3.40
6.90
0.22
iv
DMSO
20
20
20
20
21
21
21
21
dog
dog
rat
0.5
1
iv
DMSO
1.67
po
iv
20% Vit E/TPGS
DMSO
32.1
49.7
76.5
60.0
2
0.5
2.0
3.3
29.0
8.85
9.05
1.50
2.05
2.65
rat
30
0.5
1.0
2
po
iv
20% Vit E/TPGS
DMSO
dog
dog
rat
po
iv
20% Vit E/TPGS
DMSO
rat
10
po
20% Vit E/TPGS
the improved physical properties of these novel mGluR2
PAMs, led to appreciable oral bioavailability in both species.
Interestingly, when metabolite identification was again
carried out for 20, the primary site of oxidation was the tert-
butyl group. mGluR2 PAM 21 was designed to minimize this
metabolic pathway via the installation of the trifluoromethyl
group, and this change led to further improvements in
pharmacokinetics. The achievement of oral bioavailability
enabled the use of oral dosing for the assessment of efficacy
in a rat behavioral model of antipsychotic activity.
Clinically approved typical and atypical antipsychotics
and mGluR2/3 agonists have been found to block the
hyperlocomotive effects in rodents produced by psychosti-
mulants, such as PCP, and this assay is believed to be
predictive of antipsychotic potential. This model was there-
fore used here to evaluate the effect of the mGluR2 PAM 20
(Figure 5). Sprague-Dawley rats were habituated for 30 min
and then dosed with an oxazolobenzimidazole (20) or
vehicle and returned to the chambers. After another 30 min,
rats were dosed with either PCP (5.0 mg/kg, sc) or vehicle
(sc), and the activity was recorded for 90 min. Following
behavioral testing, plasma and CSF were collected from a
subset of animals to determine drug levels in these matrices.
The mGluR2 selective PAM tert-butyl phenyloxymethyl
cyano oxazolobenzimidazole (TBPCOB, 20) fully inhibited
the effect of PCP at 100 mg/kg po, a dose that resulted in
plasma and CSF levels of 86 and 1.5 μM, respectively. The
intermediate dose of 30 mg/kg also significantly attenuated
the PCP response (CSF = 550 nM), whereas the 10 mg/kg
dose failed to produce a significant effect (CSF = 70 nM).
Importantly, this stands as one of a few published examples of
mGluR2PAM efficacy14-16,23-25 in a rodent model sensitive to
clinically therapeutic antipsychotics and is notable given the
full efficacy observed with oral dosing. These data support the
notion that a selective mGluR2 PAM has antipsychotic poten-
tial similar to that seen with an mGluR2/3 agonist.26 The
observed in vivo efficacy of TBPCOB (20) is believed to be
driven by mGluR2 potentiation given that intrinsic agonism
was determined to be low (23% maximial activation and weak
EC50 = 700 nM). Rat FLIPR potency was also obtained for 20
(EC50 = 42 nM, 77% max) and found to be similar to the
human potency in further support of this notion. In addition,
TBPCOB (20) showed no activity against other mGluR's and
did not have binding affinity for targets that could produce
Figure 5. Locomotor response to PCP (5.0 mpk; sc) over the
90 min session as a function of treatment with TBPCOB 20 (10,
30, or 100 mpk; po) or vehicle (20% Vit E TPGS) in male Sprague-
Dawley rats (250-300 g) that had been pair-housed in standard
laboratory conditions. Rats were placed in activity monitors and,
after 30 min of habituation, given either vehicle or 20 and placed
back in activity monitors. After an additional 30 min, animals were
given an injection of saline or PCP. Distance traveled over the
following 90 min was summed.
inhibition of PCP-induced hyperlocomotion in this rat beha-
vioral model (D2 dopamine or 5-HT2A receptors).
In summary, an HTS-derived lead oxazolidinone was trans-
formed into a novel series of oxazolobenzimidazole mGluR2
PAMs using a ring-constraint strategy. While potency was
significantly enhanced, the physical properties and pharma-
cokinetics of this new series were initially poor. A combined
strategy of improving physical properties and blocking sites of
metabolism led to dramatic improvements in the overall
profile of these optimized compounds. Robust efficacy in
the rat hyperlocomotion model wasobservedwith oraldosing
of TBPCOB (20), and importantly, full inhibition of the PCP-
induced hyperactivity was achievable. Oxazolobenzimid-
azoles 20 and 21 therefore represent optimized leads with
druglike properties that have potential therapeutic value for
the treatment of schizophrenia.
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. Tel: þ1-215-652-5391. Fax: þ1-215-652-7310. E-mail:
robert_garbaccio@merck.com.
SUPPORTING INFORMATION AVAILABLE Additional ex-
perimental details. This material is available free of charge via the
Internet at http://pubs.acs.org.
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ACKNOWLEDGMENT We thank Joan Murphy and Dr. Charles
(14) Duplantier, A. J.; Efremov, I.; Candler, J.; Doran, A. C.; Ganong,
A. H.; Haas, J. A.; Hanks, A. N.; Kraus, K. G.; Lazzaro, J. T.; Lu, J.;
Maklad, N.; McCarthy, S. A.; O'Sullivan, T. J.; Rogers, B. N.;
Siuciak, J. A.; Spraklin, D. K.; Zhang, L. B. 3-Benzyl-1,3-oxazoli-
din-2-ones as mGluR2 positive allosteric modulators: Hit-to lead
and lead optimization. Bioorg. Med. Chem. Lett. 2009, 19, 2524.
(15) Tresadern, G.; Cid, J. M.; Macdonald, G. J.; Vega, J. A.; de Lucas,
A. I.; Garcia, A.; Matesanz, E.; Linares, M. L.; Oehlrich, D.;
Lavreysen, H.; Biesmans, I.; Trabanco, A. A. Scaffold hopping
from pyridones to imidazo [1, 2-a] pyridines. New positive
allosteric modulators of metabotropic glutamate 2 receptor.
Bioorg. Med. Chem. Lett. 2009, 175.
Ross III for HR-MS analysis.
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DOI: 10.1021/ml100115a ACS Med. Chem. Lett. 2010, 1, 406–410
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