Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia

Article abstract of DOI:10.1021/acsmedchemlett.5b00181

Herein, we report the structure-activity relationship of a novel series of (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu₅

Full text of DOI:10.1021/acsmedchemlett.5b00181

Letter
pubs.acs.org/acsmedchemlett
Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric
Modulator Clinical Candidate Targeting Schizophrenia
Susana Conde-Ceide,† Carlos M. Martínez-Viturro,† Jesus Alcazar,‡ Pedro M. Garcia-Barrantes,⊥
́
́
Hilde Lavreysen,§ Claire Mackie,∥ Paige N. Vinson,⊥,# Jerri M. Rook,⊥,# Thomas M. Bridges,⊥,#
J. Scott Daniels,⊥,# Anton Megens,§ Xavier Langlois,§ Wilhelmus H. Drinkenburg,§ Abdellah Ahnaou,§
Colleen M. Niswender,⊥,# Carrie K. Jones,⊥,# Gregor J. Macdonald,§ Thomas Steckler,§ P. Jeffrey Conn,⊥,#
Shaun R. Stauffer,⊥,# Jose Manuel Bartolome-Nebreda,*,† and Craig W. Lindsley*,⊥,#
́
́
‡
†Neuroscience Medicinal Chemistry and Discovery Sciences Lead Discovery, Janssen Research and Development, Jarama 75A,
45007 Toledo, Spain
§Neuroscience and Discovery Sciences ADME/Tox, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse,
∥
Belgium
#
⊥Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center,
Nashville, Tennessee 37232, United States
S
* Supporting Information
ABSTRACT: Herein, we report the structure−activity relationship of a novel series of
(2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent,
selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu5) positive
allosteric modulators (PAMs). On the basis of its robust in vitro potency and in vivo efficacy in
multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK
profile and an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected
as a candidate for further development.
KEYWORDS: Positive allosteric modulator (PAM), metabotropic glutamate receptor 5 (mGlu5),
4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine, VU0409551, JNJ-46778212, schizophrenia
chizophrenia is a complex and devastating psychiatric
disorder that has been managed for decades with
window and preclude development.11,12 In this Letter, we detail
a unique industrial−academic collaboration between Janssen
Research and Development and the Vanderbilt Center for
Neuroscience Drug Discovery (VCNDD)13 that led to the
discovery of a potent, selective, and orally bioavailable mGlu5
PAM clinical candidate 17a that displays robust antipsychotic
and cognition-enhancing efficacy in the absence (stimulus bias)
of direct potentiation of NMDA receptor modulation. This is
the first disclosure of the SAR and preclinical candidate profile
of 17a.
S
monoaminergic (dopamine and serotonin) targeted therapeu-
tics, resulting in adverse effect liabilities and only limited
treatment of the multiple symptom domains.1 To effectively
address this major unmet medical need, other neurotransmitter
systems and circuits, such as those of the glutamatergic system,
have emerged as high priority targets.2,3 Of these, the
metabotropic glutamate receptor subtype 5 (mGlu5), due to
its localization in brain regions implicated in schizophrenia and
its colocalization with N-methyl-D-asparatate (NMDA) recep-
tors, is of great interest in the context of the NMDA receptor
hypofunction hypothesis of schizophrenia.4−6 Positive allosteric
modulation of mGlu5, pioneered by our laboratories7,8 and now
demonstrated by multiple chemotypes and laboratories (Figure
1), has provided key target validation data in a diverse array of
preclinical antipsychotic and cognition models.6 However,
issues remain with potential target-based neurotoxicity and
seizure liability due to ago-PAM activity, high fold-shift and/or
efficacy, or other unknown mechanisms that have somewhat
diminished enthusiasm for this novel mechanism.9,10 Previous
target validation attributed the efficacy of mGlu5 PAMs, as well
as adverse effect liability, to the potentiation of NMDA receptor
currents. Emerging data on stimulus bias within allosteric
GPCR signaling, however, may offer an approach to potentially
mitigate these undesired effects that reduce the therapeutic
The Janssen−VCNDD collaboration13 initiated around the
chemical series 12 and 13, derived from independent SAR
evaluation of HTS hits 10 and 11, followed by subsequent
hybridization of the series and lead optimization (Figure
2).14−21 While the VCNDD initially retained the phenyl
acetylene moiety and explored Eastern SAR, Janssen in parallel
was optimizing the Western linker region, improving metabolic
stability, and identified the benzyloxy linker.14−20 We then
evaluated a diverse array of heterobicyclic scaffolds utilizing
optimal Eastern and Western moieties, providing novel mGlu5
PAM chemotypes, minimally represented by 14−16, which
Received: May 4, 2015
Accepted: May 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.5b00181
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ACS Medicinal Chemistry Letters
Letter
a
Scheme 1. Synthesis of Analogues 17
a
Reagents and conditions: (a) 2-phenoxyacetyl chloride, Et3N, DCM,
0 °C to rt, 1 h, 89%; (b) Dess−Martin periodinane, DCM, 1 h, rt,
86%; (c) POCl3, dioxane, 100 °C, 1.5 h, 80%; (d) LiOH, dioxane/
H2O, 120 °C, 48 h, 65%; (e) RCOCl, Et3N, DCM, 0 °C to rt, 1 h, 65−
93%.
Figure 1. Representative, first generation MPEP-site and non-MPEP-
site mGlu5 PAMs 1−9.
ketone 20 and the substrate for dehydration to yield the
bicyclic oxazole core 21 in 77% overall yield for the two steps.
Basic removal of the ethyl carbamate delivered secondary amine
22, which could be acylated under standard amide coupling
conditions or by treatment with the desired acid chloride to
afford the exocyclic amide congeners 17 in yields ranging from
65 to 93%.21
Representative SAR for this series is detailed in Table 1.
Generally, aliphatic, cycloalkyl, and nonbasic aliphatic hetero-
cyclic amides were inactive as mGlu5 PAMs. While a number of
functionalized aryl amide and 5-membered aromatic hetero-
cyclic amide congeners were moderately active, they suffered
from poor stability, solubility, and/or DMPK properties.
Uniformly, fluorophenyl amides were found to be preferred,
providing active mGlu5 PAMs 17a,e-j with EC50s ranging from
100 to 500 nM and with high efficacy (66−92% Glu Max).
Interestingly, the 3- and 4-pyridyl amides (17l and 17m) were
potent and efficacious mGlu5 PAMs, but the 2-pyridyl analogue
(17k) was inactive. Extensive in vitro and in vivo DMPK
profiling quickly eliminated the majority of analogues from
consideration as clinical candidates, as regioisomeric fluoroa-
mides 17a,e-j displayed a dynamic range of metabolic stabilities,
solubility, and PK, with most proving unfavorable in one or
more parameters. From this effort, 17a emerged as an mGlu5
PAM with the most balanced profile (vide infra) and worthy of
further development, with no species differences (activity at rat
Figure 2. Chemical evolution of a series of (2(phenoxymethyl)-6,7-
dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones 17 that pro-
vided the first mGlu5 PAM clinical candidate.14−20
mGlu5 was comparable to human (rat EC50 = 235 nM, pEC50
=
6.63 0.08, 74 2% Glu Max).22
afforded improved DMPK profiles.14−20 Further optimization
efforts incorporated a phenoxy linker19 as well as exocyclic
amide moieties in the 5,6-heterobiaryl scaffolds, which provided
series 17.
As shown in Scheme 1, analogues 17 were prepared in five
steps from commercial materials in good to excellent overall
yields.21 Racemic amino alcohol 18 was acylated with 2-
phenoxyacetyl chloride to provide 19 in 89% yield. Dess−
Martin periodinane oxidation provided the corresponding
The molecular pharmacology profile of 17a is highlighted in
Figure 3. In the presence of an EC20 concentration of
glutamate, 17a potentiates the human mGlu5 response in a
concentration-dependent manner resulting in an EC50 of 260
nM, with 84% Glu Max (Figure 3A). Analogue 17a (10 μM)
also induces ∼10-fold shift of the glutamate CRC on human
mGlu5 (Figure 3B). Moreover, 17a is an MPEP site PAM, fully
displacing [3H]-mPEPy (Figure 3C), and is highly selective for
mGlu5 relative to mGlu1−4,6−8 at 10 μM (Figure 3D).22
B
DOI: 10.1021/acsmedchemlett.5b00181
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Letter
Table 1. SAR of Analogues of mGlu5 PAM 17
Figure 3. Molecular pharmacological profile of 17a. (A) Enhanced
calcium release induced by suboptimal concentrations of glutamate
(EC20), the PAM CRC, with an EC50 for potentiation of 260 nM. (B)
Analogue 17a induces a 10-fold leftward shift of the glutamate CRC.
(C) Binding study with [3H]-mPEPy, confirming an MPEP sight PAM
(Human IC50 = 4.37 μM, 82%). (D) mGlu selectivity data (fold-shift
at 10 μM) showing that 17a is highly selective for mGlu5. Each data
point represents the mean SD (n = 3).
Western phenyl ring, was inactive at mGlu5.21 In terms of
toxicity assessment, 17a was clean in AMES, a high content
cytotoxicity assay (>30 μM) and in GSH/CN trapping studies.
In vivo pharmacokinetics for 17a were assessed across mouse,
rat, and dog (Table 2), and moderate clearance across all three
species was noted, with good half-lives and >40% oral
bioavailability across species.21
Table 2. Pharmacokinetic Parameters for 17a
a
a
a
parameter
mouse
rat
dog
dose (mg kg−1) iv/po
Cl (mL/min/kg) iv
Vdss (L/kg) iv
2.5/10
39
2.5/10
24
1/5
12
2.9
3.3
3.7
6.7
t1/2 (h) iv
1.6
2.5
Cmax (μM) po
0.83
0.5
1.08
1.5
1.01
0.5
Tmax (h) po
AUCo‑inf (ng·h/mL) po
F (%) po
1874
44
818
96
6460
51
brain/plasma (Kp)
1.0
2.3
a
Data reported as average of three animals.
a
In oral brain/plasma studies, 17a displayed excellent CNS
Calcium mobilization assay using HEK293 expressing human mGlu5;
penetration with Kps of 1.0 and 2.3, for mouse and rat,
respectively. Furthermore, 17a was also clean in a CV-relevant
ion channel panel (hERG, Ca, Na channels, IC50s >10 μM) and
was inactive in hERG patch clamp (22% inhibition @ 3 μM).
To confirm cardiovascular safety, 17a was also evaluated in an
anesthetized guinea pig and standard CV dog models where no
significant activities were noted, with a >80-fold window.
Finally, ancillary pharmacology was assessed and found to be
clean, with the exception of weak binding to MAO-B (Ki = 6.4
μM).22
In a preclinical assay predictive of antipsychotic-like activity,
reversal of amphetamine-induced hyperlocomotion (AHL), 17a
demonstrated robust dose-responsive efficacy (Figure 4) with a
maximum reversal of ∼78% at 100 mg/kg po and a minimum
effective dose (MED) of 10 mg/kg po (ED50 = 23 mg/kg).
Moreover, only partial tolerance, but maintenance of efficacy,
was noted after 7 days of subchronic dosing in this model.21
values are the average of three or more independent determinations.
Data obtained from a single experiment not replicated.
b
Evaluation of the in vitro DMPK and physiochemical
properties of 17a supported continued progression through
the preclinical candidate flowchart. Metabolic stability assess-
ment across species indicated 17a was stable to microsomal
incubation (MetStab h, r, d: 15%, 35%, 26% remaining after 15
min), low plasma protein binding was noted (fu h, r, m, d:
3.2%, 7%, 24.1%, 9.6%), and fu brain was favorable (3.7%).21
Based on the pKa (<2.0), no salts were possible; however, the
free base demonstrated acceptable solubility (8−9 mg/mL in
30% BCD, 35 μg/mL in FaSSIF). PAM 17a possessed an
exceptional cytochrome P450 profile (1A2, 2C9, 2D6, 3A4,
IC50 >25 μM), and no 3A4 TDI or induction. CYP
phenotyping indicated 2D6 and 3A4 as major contributors,
and the major metabolite, p-hydroxylation of the naked
C
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intriguing that selective mGlu5 activation can provide
antipsychotic and cognition-enhancing efficacy in the absence
of potentiating NMDA receptor function.
Based on the favorable and unique profile of 17a, human PK
predictions, based on trough plasma levels (400 ng/mL) from
rat AHL and interspecies allometric scaling, led to predicted
human clearance in the range of 1.5 to 3.6 mL/min/kg and
with half-life of 10−24 h.21 Simulations of steady state dosing
for 24 h coverage indicated 250−600 mg qd or 100−400 mg
bid in man. If the 10-fold improved efficacy of CFC was
employed (MED of 1 mg/kg), the dose required for plasma
trough coverage drops considerably.21 However, in IND-
enabling studies, chronic administration of 17a at a high dose
of 360 mg/kg po for 30 days did induce FJC staining in a small
number of rats. With limited occurrence only under high
chronic dosing, these data raise the concern about potential
human sensitivity to an mGlu5 PAM; therefore, compound
progression paused while other PAMs were profiled.
In summary, an industrial-academic collaboration between
Janssen and the VCNDD developed an orally bioavailable
mGlu5 PAM for the treatment of schizophrenia via a
fundamentally new molecular mechanism. Leveraging subject
matter and drug discovery expertise across the two teams,
coupled with a deep basic science component, enabled the joint
project team to recognize and understand signal bias as a
potential approach to afford an acceptable therapeutic window.
Based on its in vitro and in vivo pharmacological and DMPK
profiles, 17a (VU0409551/JNJ-46778212) was approved by
Janssen as a preclinical candidate, and IND-enabling studies
were initiated. Detailed findings will be reported in due course.
Figure 4. Analogue 17a has antipsychotic-like activity in rats and dose-
dependently (3−56.6 mg/kg, po) reverses AHL. #,*,∧p < 0.05 vs
VAMP group, Dunnett’s test.
Similar results were found when hyperlocomotion was induced
by MK-801 and conditioned avoidance responding (CAR) with
an ED50 of 65 mg/kg po.22 Consistent with current
antipsychotics, 17a increased prefrontal dopamine levels
(MED 10 mg/kg po) and absolutely no effect on prolactin
levels in rats or catelpsy.21 In addition, 17a also induced septal
cFos mRNA 153% (40 mg/kg po). The mGlu5 PAM 17a was
even more efficacious in several preclinical cognition models,
showing an MED of 1 mk/kg po in contextual fear conditioning
(CFC) and an MED of 3 mg/kg po in novel object recognition.
These data strongly suggest that an mGlu5 PAM may possess
broader efficacy across multiple domains of schizophrenia, with
fewer adverse events than existing antipsychotics.
ASSOCIATED CONTENT
■
S
* Supporting Information
mGlu5 has a number of potential mechanism-mediated
adverse events that must be considered and addressed before
advancing into man.9−11 Previously, we reported that pure
mGlu5 PAMs do not possess seizure/epileptiform liabilities, as
opposed to mGlu5 agonists and ago-PAMs; thus, 17a, a pure
mGlu5 PAM in multiple cell lines and native systems, would
avoid this key mechanism-based liability.11,23 Recent data with
6 suggests that mGlu5 PAMs are neurotoxic and induce
neuronal death in rodents, as assessed by increases in Fluoro-
Jade C (FJC) staining, and that this may be related to large
fold-shift and/or high efficacy.9−11 We assessed one of our
historical ago-PAMs 12 in this paradigm and, similar to the
Merck report, found FJC-positive neurons after acute, low dose
(3 mg/kg i.p.) administration as well as seizure activity.22 In
sharp contrast, we recently reported that 17a, a pure mGlu5
PAM with high efficacy and large fold-shift, at a high dose of
120 mg/kg po for four consecutive days, did not induce FJC
staining nor did it induce seizures in mice at doses >100-fold
over the MED in AHL (CNS NOAEL of 108−147 μM·h).22
Moreover, chronic dosing at 450 mg/kg po for 14 days also
failed to elicit seizure activity in rats. The question at hand is
what distinguished 17a from other mGlu5 PAMs. As expected,
17a potentiates DHPG-induced long-term depression (LTD)
and induces calcium mobilization and ERK phosphorylation;
however, 17a does not potentiate mGlu5 modulation of NMDA
receptor currents nor NMDA receptor-dependent long-term
potentiation (LTP), suggesting a unique signal bias for this
mGlu5 PAM that may contribute to the observed, favorable
therapeutic window.22 From a conceptual point of view, it is
General methods for the synthesis and characterization of all
compounds, and methods for the in vitro and in vivo DMPK
protocols and supplemental figures. The Supporting Informa-
tion is available free of charge on the ACS Publications website
at DOI: 10.1021/acsmedchemlett.5b00181.
AUTHOR INFORMATION
■
Corresponding Authors
*Phone: 1 615-322-8700. Fax: 1 615-936-4381. E-mail: craig.
lindsley@vanderbilt.edu.
*Phone: +34 925 245778. Fax: +34 925 245771. E-mail:
jbartolo@its.jnj.com.
Author Contributions
C.W.L., J.M.B., P.J.C., S.R.S., C.M.N., and C.J.K. drafted/
corrected the manuscript. C.M.V., J.A., P.M.G., and J.M.B.
performed the chemical synthesis. C.W.L., J.M.B., P.J.C., S.R.S.,
C.M.N., J.M.K., C.J.K., T.S., G.M., C.M., and H.L. oversaw the
target selection and interpreted the biological data. J.S.D.,
T.M.B., and C.M. performed the in vitro and in vivo DMPK
studies. T.S., A.M., X.L., W.H.D., A.A., and C.K.J. performed
the in vivo experiments. All authors have given approval to the
final version of the manuscript.
Notes
The authors declare the following competing financial
interest(s): Both VCNDD and JNJ are actively developing
mGlu5 PAMs as therapeutic agents.
D
DOI: 10.1021/acsmedchemlett.5b00181
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ACS Medicinal Chemistry Letters
Letter
signaling profiles of positive allosteric modulators of mGlu5 determine
differences in in vivo activity’. Biol. Psychiatry 2013, 73, 501−509.
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Opportunities and challenges in the discovery of allosteric modulators
of GPCRs for the treatment of CNS disorders. Nat. Rev. Drug
Discovery 2014, 13, 692−708.
ACKNOWLEDGMENTS
■
The authors would also like to thank Dr. Brian Hrupka, Heidi
Huysmans, Christ Nolten, Gerd Van Den Kieboom, and Sofie
Versweyveld for their contribution with animal surgery and data
collection.
(13) MacDonald, G. J.; Lindsley, C. W. A unique industrial-academic
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(16) Manka, J.; Zhou, Y.; Williams, R.; Weaver, C. D.; Dawson, E. S.;
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(17) Noetzel, M. J.; Gregory, K. J.; Vinson, J. T.; Manka, S. R.;
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(18) Bartolome-Nebreda, J. M.; Conde-Ceide, S.; Delgado, F.; Pas
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Stauffer, S. R.; Jadhav, S.; Days, E.; Weaver, C. D.; Lindsley, C. W.;
Niswender, C. M.; Jones, C. K.; Conn, P. J.; Rombouts, F.; Lavreysen,
H.; Macdonald, G. J.; Mackie, C.; Steckler, T. Dihydrothiazolopyr-
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(19) Turlington, M.; Malosh, C.; Jacobs, J.; Manka, J. T.; Vinson, P.
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Bartolome, J. M.; Macdonald, G. J.; Steckler, T.; Daniels, J. S.; Weaver,
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ABBREVIATIONS
■
DCM, dichloromethane; AHL, amphetamine-induced hyper-
locomotion; CFC, contextual fear conditioning; MED,
minimum effective dose; LTD, long-term depression; metab-
otropic glutamate receptor, (mGlu); FJC, fluorjade; PAM,
positive allosteric modulator
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DOI: 10.1021/acsmedchemlett.5b00181
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX