Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5

Article abstract of DOI:10.1021/acsmedchemlett.5b00450

Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents.

Full text of DOI:10.1021/acsmedchemlett.5b00450

Letter
pubs.acs.org/acsmedchemlett
Discovery and Preclinical Evaluation of BMS-955829, a Potent
Positive Allosteric Modulator of mGluR5
Fukang Yang,* Lawrence B. Snyder, Anand Balakrishnan, Jeffrey M. Brown, Digavalli V. Sivarao,
Amy Easton, Alda Fernandes, Michael Gulianello, Umesh M. Hanumegowda, Hong Huang,
Yanling Huang, Kelli M. Jones, Yu-Wen Li, Michele Matchett, Gail Mattson, Regina Miller,
Kenneth S. Santone, Arun Senapati, Eric E. Shields, Frank J. Simutis, Ryan Westphal, Valerie J. Whiterock,
Joanne J. Bronson, John E. Macor, and Andrew P. Degnan
Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
*
S Supporting Information
ABSTRACT: Positive allosteric modulators (PAMs) of the
metabotropic glutamate receptor subtype 5 (mGluR5) are of
interest due to their potential therapeutic utility in
schizophrenia and other cognitive disorders. Herein we
describe the discovery and optimization of a novel
oxazolidinone-based chemotype to identify BMS-955829 (4),
a compound with high functional PAM potency, excellent
mGluR5 binding affinity, low glutamate fold shift, and high
selectivity for the mGluR5 subtype. The low fold shift and
absence of agonist activity proved critical in the identification
of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel
object recognition models in rodents.
KEYWORDS: mGluR5, positive allosteric modulator, schizophrenia, cognition, neurotoxicity
chizophrenia is a serious brain disorder that distorts the
excitatory neurotransmitter in the human brain and plays a key
physiological role in a wide variety of processes. Glutamatergic
6
S
way a person thinks, acts, expresses emotions, perceives
1
reality, and relates to others. Some of the most common
symptoms include delusions, hallucinations, disorganized
speech, disorganized or catatonic behavior, and affective
neurotransmission occurs mainly through activation of cell
surface receptors, including ligand-gated ion channels (iono-
tropic receptors) and metabotropic glutamate G protein
coupled receptors (GPCRs). The metabotropic glutamate
receptor family (mGluRs) consists of eight family members
that are part of the family 3 GPCR superfamily. These receptors
are further subdivided into Group I (mGluR 1, 5), Group II
(mGluR 2, 3), and Group III (mGluR 4, 6, 7, 8) based upon
2
flattening. The onset of symptoms usually occurs in young
3
adults, with a global lifetime prevalence of 0.3−0.7%. The
incidence of schizophrenia, without regard to severity or
classification, has been estimated to be ∼1% of the United
States population or roughly 3.2 million people. Of these 3.2
million people, it is estimated that 60% are using some form of
healthcare, which in 2002, cost an estimated $63 billion dollars
in the U.S. alone. Tragically, schizophrenia patients die 12−15
years earlier than the general population. While antipsychotic
drugs are available to treat schizophrenia, most result in
difficult-to-manage side effects such as blurred vision,
7
sequence homology, receptor signaling, and pharmacology.
The mGlu5 receptor is expressed broadly throughout the
8
CNS with predominantly postsynaptic localization. mGluR5 is
a Gαq-coupled receptor that activates phospholipase C and
elevates intracellular calcium levels, resulting in activation of
downstream signaling molecules. Recent studies in mGluR5
knockout mice using small molecules that negatively modulate
mGluR5 function suggested that blocking mGluR5 function
may have therapeutic utility in CNS and peripheral disease
states including, pain, anxiety, gastroesophageal reflux (GERD),
Parkinson’s disease levodopa-induced dyskinesia, and fragile X
4
drowsiness, dizziness, and extrapyramidal symptoms. Further-
more, atypical antipsychotic medications can cause significant
weight gain and changes in metabolism, resulting in an
5
increased risk of diabetes and high cholesterol. As a result,
weight, glucose levels, and lipid levels need to be regularly
monitored by a healthcare professional, causing an extra burden
on the patient and additional healthcare costs.
9
syndrome. The potential for therapies based upon the negative
modulation of mGluR5 is somewhat limited by side effects such
Schizophrenia has long been attributed to an excess of
dopamine in certain pathways of the brain. More recent
evidence implicates N-methyl-D-aspartate (NMDA) receptor
hypofunction in the glutamate system. Glutamate is the major
Received: November 23, 2015
Accepted: January 3, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.5b00450
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
1
0
as deficits in memory, learning, and sensory processing.
our starting point, we set as our goals for the lead optimization
efforts: a) to determine the minimum pharmacophore
necessary for potent activity; b) increase potency; c) reduce
protein binding; and d) minimize time-dependent CYP
inhibition. We first examined replacement of the methoxy
group with a 3-fluoro moiety leading to 2, which retained the
excellent glutamate shift response (fs = 6.0) and exhibited a
slight increase in potency. Furthermore, 2 was devoid of the
time-dependent CYP3A4 inhibition observed with 1. We next
turned our sights toward opportunities to enhance free fraction.
To this end, the phenyl “B-ring” of 2 (Figure 1) was replaced
with the more polar pyridine to afford compound 3. While
increases in free fraction were negligible, compound 3 proved
to be 30 times more potent than initial screening hit 1 (Table
1). Unfortunately, intraperitoneal (ip) administration of
compound 3 to C57/Bl6 mice at 3 mg/kg induced convulsions
and, in some cases, death (1/4 mice). The finding of
convulsions (presumably indicative of underlying seizures) in
mice was surprising, as there had been no prior reports of
Conversely, mGluR5 positive allosteric modulators (PAMs)
have been shown to positively impact cognition in a variety of
animal models, to exhibit efficacy in animal models of
1
1
1
2,13
psychosis,
and to enhance EEG power, which is indicative
14
of an increased state of arousal. Taken together, these in vivo
preclinical findings support the use of mGluR5 PAMs for the
treatment of schizophrenia.
Our medicinal chemistry effort began prior to the reports of
15−17
mGluR5 PAM-based seizures and neurotoxicity.
At that
time, we targeted the identification of a potent positive
allosteric modulator with high in vitro efficacy in the hopes
that a high fold shift compound would maximize the potential
for robust in vivo efficacy. It was in this context that we
undertook an mGluR5 PAM screening effort, which resulted in
the identification of lead 1. Herein we describe the optimization
of lead 1 to identify compound 4 (BMS-955829), a potent and
selective positive allosteric modulator of mGluR5.
Oxazolidinone 1 (Figure 1) was identified from a high
throughput screening campaign and shown to possess an EC50
20
mGluR5 PAMs causing convulsions.
During the course of our medicinal chemistry effort, we were
fortunate to have identified a number of useful tool compounds
with a wide range of pharmacologies. Two such tool
compounds are illustrated in Figure 2. PAM 5 was also found
Figure 2. Structurally related tool compounds used in pharmacological
blockade experiment.
Figure 1. Evolution of 1 to BMS-955829 (4).
to cause convulsions in mice (@10 mg/kg ip, n = 4) while the
structurally-related silent allosteric modulator (SAM) 6 did not
(@30 mg/kg ip, n = 4). Coadministration of PAM 5 and SAM
6 demonstrated complete pharmacological blockade of
convulsions, strongly suggesting that the convulsions were
mechanism-based.
of 29 nM for PAM activity in a FLIPR-based mGluR5
1
8
functional assay (Table 1). MPEPy is a small molecule ligand,
19
which binds to the MPEP allosteric site of mGluR5. In a
3
binding experiment using H-MPEPy as the radiolabeled ligand,
1
had binding affinity in good agreement with its functional
Until this point, we had targeted a compound with a high
glutamate fold shift in order to maximize the probability for in
vivo efficacy. With the finding of convulsions, however, we
reconsidered this approach. Instead, we decided to test the
hypothesis that a low fold shift compound might maintain
efficacy in rodent models relevant to schizophrenia while
mitigating or eliminating the convulsion liability. Earlier
potency (K = 13 nM). The glutamate fold shift (fs = 7.1) was
at a level consistent with that required to achieve in vivo
i
11−14
efficacy in the literature.
pure PAM, lacking any inherent mGluR5 agonist activity up to
0 μM. While 1 had good microsomal stability, further
evaluation revealed potent time-dependent cytochrome P450
CYP3A4) inhibition and extensive protein binding. Using 1 as
Compound 1 was found to be a
3
21
(
structure−activity relationships indicated that fold shift was
Table 1. Biological Data for Compounds 1−6
a
a
a
b
a
compd PAM EC50 (nM) MPEPy K (nM) glutamate EC50 shift TD HLM-CYP3A4 agonist EC50 (μM) protein binding (%) convulsions (dose)
i
1
2
3
4
5
6
29 ± 2
15 ± 8
0.83 ± 0.08
2.6 ± 1.0
6.0 ± 1.5
>3000
13 ± 1
7.1 ± 0.1
6.0 ± 0.8
8.7 ± 0.7
2.4 ± 0.1
7.1 ± 0.5
NA
9
1
1
1
1
1
>30
99.7
NA
no (10 mg/kg)
NA
c
6.5 ± 1.3
1.5 ± 0.1
1.6 ± 0.4
25 ± 5
>30
>30
99.6
99.3
96.5
99.4
yes (3 mg/kg)
no (30 mg/kg)
yes (10 mg/kg)
no (30 mg/kg)
>30
d
0.31 ± 0.05
>3
10 ± 8
a
Data represents mean ± SEM (≥2 replicates). Ratio of CYP3A4 inhibition from 30 to 5 min using BFC as the substrate. c3H-MPEP used in place
b
3
d
of H-MPEPy as radioligand. Agonist activity was confirmed in primary rat cortical astrocytes, which showed comparable expression to HEK
transfected cells (Bmax: HEK-mGLuR5 10.9 pmol/mg; Astrocytes 6.6 pmol/mg).
B
DOI: 10.1021/acsmedchemlett.5b00450
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ACS Medicinal Chemistry Letters
Letter
exquisitely sensitive to the substitution pattern on the
fluorophenyl “D-ring.” Further optimization of this aryl ring
led us to compound 4 (BMS-955829, Figure 1), which differed
from 3 only by addition of a single fluorine atom. Compound 4
was found to be a potent mGluR5 PAM (EC = 2.6 ± 1.0 nM;
designed to mimic the pronounced deficits in cognitive and
executive function found in patients with schizophrenia. The
novel object recognition (NOR) assay was designed to exploit a
rodent’s instinctive proclivity to explore novel objects at the
expense of familiar ones to assess their capacity for episodic
recognition. Compound 4 was administered subcutaneously
(sc) to mice 60 min prior to training on day 1. On day 2, one of
the familiar objects was replaced with a novel object and time
spent with each object was recorded. Figure 3 illustrates results
5
0
28
n = 6), devoid of inherent mGluR5 agonist activity (EC > 30
50
μM). The measured binding K of 4 was found to be 1.6 nM,
i
which was in good agreement with its functional potency.
Against a panel of related mGluR receptors (1−4 and 6−8), 4
was shown to be completely selective for mGluR5, lacking any
measurable PAM, NAM, or agonist activity at other mGluRs
(
>10 μM). The main differentiator of 4 from other analogues in
this series was its remarkably low glutamate fold shift (fs = 2.4).
Based on the in vitro profile of 4, we felt that this compound
was a good candidate to explore our hypothesis that a decrease
in glutamate fold shift would decrease convulsions. Gratifyingly,
when compound 4 was administered to mice, no convulsions
were observed up to the maximum dose examined (30 mg/kg,
ip). In conjunction with this experiment, ex vivo occupancy
experiments showed that the mGlu5 receptors were essentially
saturated at both the 10 and 30 mg/kg doses (94%), suggesting
elimination of the convulsion risk with a low fold shift PAM.
The medicinal chemistry route adopted to prepare 4 (BMS-
955829) is illustrated in Scheme 1. Diethylphosphonate 8 was
Figure 3. Dose response of 4 in mouse novel object recognition.
a
Scheme 1. Synthesis of 4 (BMS-955829)
obtained with compound 4. Mice dosed with 0.3, 1, or 3 mg/kg
showed significant reductions in time spent with the familiar
object, indicating improved recognition memory. Plasma
concentrations and ex vivo receptor occupancy data were
obtained using satellite animals and indicated total plasma
levels of 116 ± 5 nM, total brain levels of 178 ± 13 nM, and
1
8% receptor occupancy at the minimum efficacious dose
(
MED) of 0.3 mg/kg.
In humans, executive function is typically measured using an
intradimensional/extra-dimensional (ID/ED) shift task or the
29,30
Wisconsin card sorting test (WCST).
The rat set-shifting
experiment was designed to be a rodent analogue of the WCST
where the observed ED behavior has been shown to be
mediated by the prefrontal cortex (PFC), a region of the brain
implicated in mediating working memory for spatial and visual
a
Reagents and conditions: (a) P(OEt) , 160 °C, 2−4 h, 93−100%; (b)
3
3
1
5
-bromonicotinaldehyde, potassium t-butoxide, −10 °C, THF; (c)
object information. On day 1, rats were trained to
discriminate on the basis of the first dimension (brightness:
light versus dark). Twenty-four hours later, rats were
administered MK-801 (an NMDA antagonist used to mimic
K OsO ·2H O, t-butylcarbamate, (DHQD) PHAL, t-BuOCl, NaOH
2
4
2
2
(
0.5 M), H O/propanol, 0 to 22 °C, 16 h, 32−35%; (d) HCl 4 M in
2
dioxane, 50 °C, 3 h; (e) CDI, Hu
̈
nig’s base, THF, 23−72%; (f)
ethynylbenzene, PdCl (PPh ) , PPh , CuI, TEA, reflux, 18 h, 60−85%.
2
3
2
3
32
observed deficits in executive function) along with varying
doses of 4 and tested against the second dimension (texture:
rough versus smooth), recording the number of trials needed
until rats achieved the preselected criterion (eight consecutive
correct selections). Figure 4 illustrates results obtained with
compound 4. Rats that received 0.1, 0.3, 1, or 3 mg/kg of 4
showed significant reductions in the number of trials required
to achieve criterion, indicating reversal of MK-801 induced
deficits in executive function. As in the mouse NOR
experiment, plasma concentrations and ex vivo occupancy
were obtained using satellite animals and indicated total plasma
levels of 34 ± 4 nM, total brain levels of 34 ± 3 nM, and 19%
receptor occupancy at the minimum efficacious dose (MED) of
0.1 mg/kg.
2
2
prepared via a Michaelis−Arbuzov reaction, employing benzyl
23
bromide 7. Horner−Wadsworth−Emmons olefination with
-bromonicotinaldehyde afforded stilbene 9. Asymmetric
provided 10 in moderate yield,
affording both possible regioisomers (desired/undesired =
:1). Separation of the regioisomers by flash chromatography,
removal of the Boc group under acidic conditions, and
cyclization of the resulting aminoalcohol with carbonyldiimi-
dazole afforded oxazolidinone 12 in 99% ee. Completion of
the synthesis via a palladium-mediated Sonogashira cross
coupling with ethynylbenzene provided 4.
While the lack of convulsions upon administration of 4 was
encouraging, we needed to determine whether an mGluR5
PAM with a low glutamate fold shift would be efficacious in
preclinical behavioral models relevant to schizophrenia. We
investigated the efficacy of 4 in multiple rodent models
5
24,25
aminohydroxylation
4
26
2
7
Given its robust in vivo efficacy and low potential for
convulsions, compound 4 was further subjected to a battery of
in vitro testing designed to evaluate its potential for drug−drug
interactions and toxicity. Against a panel of eight recombinant
C
DOI: 10.1021/acsmedchemlett.5b00450
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ACS Medicinal Chemistry Letters
Letter
PAMs possessing a low fold shift (∼2). A more detailed
disclosure of preclinical efficacy, metabolism, pharmacokinetics,
toxicology, and SAR studies leading to the discovery of BMS-
9
55829 will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00450.
Experimental procedures for the preparation of com-
pound 4, characterization data for 1−6, X-ray crystal
structure of 4, biological experimental methods, a
summary of PK parameters for compound 4, and
representative slides from the rat neurotoxicity study
Figure 4. Compound 4 reverses MK-801 deficit in rat set-shifting.
human CYP isoforms, 4 showed low levels of inhibition (IC s
(PDF)
50
≥
1.3 μM). Compound 4 had a measured IC50 of 3.6 μM in a
AUTHOR INFORMATION
hERG patch clamp experiment, but given the very low exposure
required for efficacy and the high protein binding of 4, the
potential for QT related electrocardiographic findings was
deemed to be low. There was minimal inhibition in a sodium
patch clamp experiment (∼40% @ 10 μM), indicating little risk
of affecting cardiac conduction. Compound 4 was tested in a
broad panel of receptor and ion channel binding assays, which
identified a potential interaction with the progesterone receptor
■
Corresponding Author
*Tel: 1-203-677-7675. Fax: 1-203-677-7702. E-mail: fukang.
yang@bms.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(
IC50 = 2.3 μM). Follow-up in a progesterone functional assay
We thank Dr. Hyunsoo Park and Dr. Qi Gao for X-ray crystal
structure determination of compound 4, and Ling Yang for
assistance with preparation of the manuscript. We also thank
members of Discovery Analytical Sciences for detailed
characterizations and members of the Department of Chemical
Synthesis for scale-up of 4 and its intermediates.
demonstrated no significant agonist or antagonist activity at this
receptor. Compound 4 was negative in the in vitro micro-
nucleus assay and in an Ames mutagenicity assay, both in the
presence and absence of S9 liver fractions, indicating a low
potential for genetic toxicity.
The oral bioavailability of compound 4 was examined in
multiple species where it ranged from good to excellent (rat
18
ABBREVIATIONS
BFC, 7-benzyloxy-4-trifluoromethylcoumarin; CYP, cyto-
chrome P450; CNS, central nervous system; (DHQD) PHAL,
Fpo = 100%, dog Fpo = 68%, and cyno Fpo = 50%). In rat, 4
showed low clearance at 11 mL/kg/min, low volume of
distribution (1.8 L/kg), and favorable brain uptake (B/P ≈ 1).
A recent disclosure of Parmentier-Batteur et al. reported that
repeat dosing of high fold shift PAMs (fs = 6−22) resulted in
neurotoxicity. The neurotoxicity was characterized by
moderate to severe neuronal necrosis particularly in the
auditory complex and hippocampus. On the basis of their
studies, the authors speculated that it may be possible to
identify a compound with an acceptable margin of safety if fold
shift was capped at ∼2. Indeed, H&E stained sections of the
brain, including the auditory complex and hippocampus,
showed no evidence of necrosis in rats administered oral
■
2
hydroquinidine 1,4-phthalazinediyl diether; EEG, electroence-
phalography; FLIPR, fluorometric imaging plate reader; fs, fold
shift; GERD, gastroesophageal reflux; Glu, glutamate; HLM,
human liver microsome; IND, investigational new drug; ip,
intraperitoneal; MED, minimum efficacious dose; mGluR5,
metabotropic glutamate receptor 5; MK-801, dizocilpine;
MPEP, 2-methyl-6-(phenylethynyl)pyridine; MPEPy, 3-me-
thoxy-5-pyridin-2-ylethynylpyridine; NAM, negative allosteric
modulator; NMDA, N-methyl-D-aspartate; NOR, novel object
recognition; PAM, positive allosteric modulator; SAM, silent
allosteric modulator; sc, subcutaneous
1
6
doses of 4 at 100 mg/kg/day for 8 days (day 1: C = 41 μM;
max
18
AUC0−24 = 751 μM·h). Upon repeat dosing for 2 weeks in
rats and for 5 days in dog, 4 demonstrated an acceptable margin
of safety. On the basis of its favorable efficacy and safety
profiles, 4 advanced into IND-enabling toxicology studies.
In conclusion, we have described the discovery of BMS-
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55829 (4), a potent and selective positive allosteric modulator
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DOI: 10.1021/acsmedchemlett.5b00450
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX