The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate

Article abstract of DOI:10.1016/j.bmcl.2018.10.050

This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu₄ positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled a

Full text of DOI:10.1016/j.bmcl.2018.10.050

Accepted Manuscript
The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK chal-
lenges en route to an mGlu4 PAM development candidate
Joseph D. Panarese, Darren W. Engers, Yong-Jin Wu, Jason M. Guernon, Aspen
Chun, Alison R. Gregro, Aaron M. Bender, Rory A. Capstick, Joshua M.
Wieting, Joanne J. Bronson, John E. Macor, Ryan Westphal, Matthew Soars,
Julie E. Engers, Andrew S. Felts, Kyle A. Emmitte, Carrie K. Jones, Anna L.
Blobaum, P. Jeffrey Conn, Colleen M. Niswender, Corey R. Hopkins, Craig W.
Lindsley
PII:
S0960-894X(18)30853-9
https://doi.org/10.1016/j.bmcl.2018.10.050
BMCL 26109
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 September 2018
29 October 2018
30 October 2018
Please cite this article as: Panarese, J.D., Engers, D.W., Wu, Y-J., Guernon, J.M., Chun, A., Gregro, A.R., Bender,
A.M., Capstick, R.A., Wieting, J.M., Bronson, J.J., Macor, J.E., Westphal, R., Soars, M., Engers, J.E., Felts, A.S.,
Emmitte, K.A., Jones, C.K., Blobaum, A.L., Conn, P.J., Niswender, C.M., Hopkins, C.R., Lindsley, C.W., The
discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM
development candidate, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.
2018.10.050
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The discovery of VU0652957 (VU2957, Valiglurax):
SAR and DMPK challenges en route to an mGlu4
PAM development candidate
Leave this area blank for abstract info.
Joseph D. Panarese, Darren W. Engers, Yong-Jin Wu, Jason M. Guernon, Aspen Chun, Alison R, Gregro, Aaron M. Bender,
Rory A. Capstick, Joshua M. Wieting, Joanne J. Bronson, John E. Macor, Ryan Westphal, Matthew Soars, Julie L. Engers,
Andrew S. Felts, Alice L. Rodriguez, Kyle A. Emmitte, Carrie K. Jones, Anna L. Blobaum, P. Jeffrey Conn, Colleen M.
Niswender, Corey R. Hopkins and Craig W. Lindsley
R1
CF3
potency
6,6-ring
systems
F
Z
X
Y
N
N
N
N
HN
PK
HN
HN
N
Cl
N
N
X
R
N
efficacy
formulation
H
H
H
N
Y
W,X,Y,Z = CH, N
VU0418506
VU2957 (Valiglurax)
100s of analogs

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges
en route to an mGlu4 PAM development candidate
Joseph D. Panarese,a,b Darren W. Engers,a,b Yong-Jin Wu,c Jason M. Guernon,c Aspen Chun,a,b Alison R.
Gregro,a,b Aaron M. Bender,a,b Rory A. Capstick,a,b Joshua M. Wieting,a,b Joanne J. Bronson,c John E.
Macor,c Ryan Westphal,c Matthew Soars,c Julie E. Engers,a,b Andrew S. Felts, a,b Kyle A. Emmitte,a,b Carrie
K. Jones,a,b Anna L. Blobaum,a,b P. Jeffrey Conn,a,b,f, Colleen M. Niswender,a,b,f Corey R. Hopkins,a,b* and
Craig W. Lindsley a,b,d,e*
aVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA
bDepartment of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
cBristol-Myers Squibb Co., Research & Development, 5 Research Parkway, Wallingford, CT 06492 USA
dDepartment of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
eDepartment of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA
fVanderbilt Kennedy Center, Vanderbilt University, Nashville, TN 37232, USA
*To whom correspondence should be addressed: corey.hopkins@umnc.edu or craig.lindsley@vanderbilt.edu
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of
a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of
VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate.
Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as
subtle structural changes affecting overall physiochemical/DMPK properties and CNS
penetration).
Keywords:
mGlu4
Metabotropic glutamate receptor
Positive allosteric modulator (PAM)
Parkinson’s disease (PD)
Structure-Activity Relationship (SAR)
2018 Elsevier Ltd. All rights reserved.
The metabotropic glutamate receptor subtype 4 (mGlu4) has
been a target of interest for a non-dopaminergic approach for
the palliative, and potentially, disease modifying treatment of
Parkinson’s disease (PD)1-6 since the discovery of the first
mGlu4 positive allosteric modulator (PAM), (-)-PHCCC (1), in
the early 2000s.7,8 The path forward to the clinic was
challenging, as mGlu4 allosteric ligands (Figure 1) suffered
from poor physicochemical properties, poor pharmacokinetics
(PK), undesired ancillary pharmacology, limited CNS
exposure and/or CYP inhibition/induction issues.9-16 While
many mGlu4 PAMs failed to advance into IND-enabling
studies, they did provide in vivo target validation, and further
increased interest in the target and mechanism. Only recently,
PAM 6, derived from 1, entered clinical development.17 In
parallel, our labs developed 4, which failed to advance due to a
CYP1A2 auto-induction of metabolism liability;12 however,
next generation analogs 7 and 8 mitigated the issue.15,16 Further
optimization afforded VU2957 (9), a novel mGlu4 PAM that,
with a spray-dried dispersion (SDD) formulation, emerged as a
preclinical development candidate.16 The SAR leading to 9 is
disclosed herein.
OH
N
O
N
S
NH
N
N
H
N
N
Cl
N
N
N
H
H
O
O
1
2
)
3
ADX88178 ( )
(-)-PHCCC (
)
VU0364770 (
O
O
N
OH
N
NH2
O
F
HN
N
N
Cl
HN
Cl
Cl
H
N
S
O
N
4
)
Lu AF21934 (
5
)
6
PXT002331, Foliglurax ( )
VU0418506 (
F
F
O
CF3
NH
N
N
HN
HN
N
HN
N
N
N
N
N
N
S
N
N
H
N
H
H
N
9
VU2957, Valiglurax (
)
8
VU6001376 (
)
7
VU0550054 (
)

14.6 mL/min/kg). The CYP profile of 12b was problematic,
with potent inhbition of multiple isoforms (1A2 IC50 = 0.15
M, 2C9 IC50 = 1.35 M, 2D6 IC50 = 3.98 M, 3A4 IC50 = 0.44
M); however, we anticipated that modulation of the
electronics of the isoquinoline moiety could address these
issues. In vivo in rat, 12b was suprahepatically cleared (CLp =
424 mL/min/kg, t1/2 = 10.8 min, Vss = 4.88 L/kg), failing to
display an in vitro/in vivo correlation (IVIVC). Follow-up
Figure 1. Structures representative of mGlu4 PAMs 1-9. PAMs 1-5, 7
and 8 are preclinical tool compounds, while 6 in currently in Phase II and
9 was advanced as a preclinical development candidate.
Utilizing 4 as a ‘new’ lead (Figure 2), we explored 5,6-
heterobicyclic ring systems to replace the 3-chloro-4-
fluorophenyl moiety, and discovered PAMs 7 and 8,14,15 which
mitigated the CYP1A2 liability and further validated the target
in preclinical PD models, but were unsuitable as preclinical
development candidates (due to low oral exposure in higher
species). Next, we surveyed a variety of 6,6-heterobicyclic
systems 10, and, after hundreds of analogs were synthesized
and profiled, we discovered VU2957 (9), an mGlu4 PAM with
a profile suitable for clinical development.18 However, the path
to 9 was not straightforward. Here, we describe for the first
time the optimization campaign (SAR and DMPK profiles of
diverse analogs 10) that led from 4 to VU2957 (9). For all the
analogs described herein, the NH-linker was essential for
mGlu4 PAM activity. N-alkyation, replacement of the NH with
other heteroatoms (O and S) or carbon-linked congeners were
devoid of mGlu4 PAM activity.
N
HN
6,6-core
N
H
N
12
N
N
N
N
12a
12b
12c
12d
EC50 = 402 nM
(97% Glu Max)
EC50 = 75 nM
(145% Glu Max)
EC50 = 730 nM
(59% Glu Max)
EC50 >10 M
N
N
N
N
N
N
12f
12h
12g
12e
EC50 >10 M
EC50 >10 M
EC50 >10 M
EC50 >10 M
fused 5,6- and
6,6-heterocycles
5,6-ring
7
8
and
Figure 3. Structures and mGlu4 PAM potencies of analogs 12.
systems
F
N
HN
6,6-ring
systems
R1
Z
N
Cl
studies found that 12b was subject to significant NADPH-
independent metabolism (possibly AO or XO). Further
optimization efforts included blocking the positions  to the
isoquinoline nitrogen, installing electron-withdrawing
substituents to electronically tune the ring system, and
introducing steric bulk.
H
Z
Z
N
X
Y
N
HN
9
N
X
R
H
4
)
VU0418506 (
Y
W,X,Y,Z = CH, N
10
Figure 2. Optimization plan for 4 to develop an mGlu4 PAM suitable for
clincial development, resulting in VU2957 (9).
Scheme 2. Synthesis of mGlu4 PAMs analogs 15 and 17.a
Scheme 1. Synthesis of mGlu4 PAM analogs 12.a
(i)
NR1R2
O-
+
N
N
HN
a
b,c,d
N
Z
Z
Z
Z
N
X
Y
N
N
HN
Z
Z
Z
Z
H
Br
Br
a,b
X
Y
N
N
H
13
14
14
15
Br
N
X,Y,Z = CH, N
R
(ii)
Cl
N
N
HN
11
12
e
N
b,c,f
N
H
Br
aReagents and conditions: (a) 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-
b]pyridine-3-amine, 5 mol% Pd2(dba)3, 5 mol% XantPhos, Cs2CO3, 1,4-
dioxane, wave, 140 °C, 30 min, 65-75%; (b) TFA, toluene, 100 °C, 30 min,
80-84%.
N
16
17
aReagents and conditions: (a) mCPBA, CH2Cl2, 78%; (b) 1-(4-
methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-3-amine, 5 mol% Pd2(dba)3, 5
mol% XantPhos, Cs2CO3, 1,4-dioxane, wave, 140 °C, 30 min, 80%; (c) TFA,
toluene, 100 °C, 30 min, 83-89%; (d) PyBroP, HNR1R2, DEIPA, CH2Cl2, 53-
80%; (e) POCl3, DCE, 80 °C, 78%; (f) RB(OH)2 or RBF3K, Cs2CO3, 5 mol%
Pd(dppf)Cl2, H2O:1,4-dioxane (1:3), wave, 125 °C, 1h, 48-82%.
We envisioned a number of potential 6,6-ring systems to
evaluate as mGlu4 PAMs, and we initially explored a variety of
unsubstituted ring systems to narrow down the scope prior to
delving into more laborious chemistry of substituted analogs.
As shown in Scheme 1, a standard Buchwald coupling with 1-
(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-3-amine,
followed by TFA deprotection delivered analogs 12. SAR was
steep, with only naphthylene 12a (EC50 = 402 nM, 97%
GluMax), isoquinoline 12b (EC50 = 75 nM, 145% GluMax),
and quinoline 12c (EC50 = 730 nM, 59% GluMax) displaying
PAM activity. All other scaffolds were inactive (EC50 > 10
M). Due to its superior potency and efficacy, 12b (MW =
261, clogP = 3.2) was further profiled in a battery of in vitro
and in vivo DMPK assays. PAM 12b showed favorable protein
binding (fu (r,h) = 0.046, 0.092), brain homogenate binding (r
To address these liabilities, we synthesized and assessed
amine-based analogs 15 and carbon-linked congeners 17 via a
4- to 5-step synthetic route (Scheme 2). The commercial 6-
bromoisoquinoline 13 was converted to the corresponding N-
oxide 14, which then underwent a standard Buchwald coupling
with
1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-3-
amine, followed by TFA deprotection. Treatment with PyBroP
and an amine afforded analogs 15 in yields ranging from 53-
80%. N-oxide 14 could also be smoothly converted into the -
chloro isoquinoline 16 and then subjected to a Suzuki coupling
fu = 0.029) and low predicted hepatic clearance in rat (CLhep
=

protocol to provide analogs 17 in good isolated yield and
chemical diversity.
Turning our attention to carbon-based moieties  to the
isoquinoline nitrogen (Analogs 17, Table 2) proved more
productive in terms of mGlu4 PAM activity (EC50s 8 to 132
nM), but DMPK profiles were mixed. Simple alkyl congeners,
such as 17a and 17b, possessed unacceptable levels of
CYP1A2 inhibition (IC50’s < 1 M) and had no detectable brain
levels in rat. More lipophilic variants, such as the
difluoromethyl derivative 17c, was an extremely potent PAM
(EC50 = 8.3 nM, 99% Glu Max), with moderate predicted
hepatic clearance (CLhep of 12.2 and 30.7 mL/min/kg for
human and rat, respectively), good plasma protein binding (fus
0.030 and 0.032 for rat and human, respectively) and excellent
CNS penetration in rat (Kp = 2.2). These favorable properties
translated into robust efficacy in a rat haloperidol-induced
catalepsy (HIC) model,17 with a 3.0 mg/kg PO dose of 17c
affording a 45% reversal of catalepsy (1.5 mg/kg haloperidol,
n = 8). However, CYP1A2 inhibition (IC50 = 300 nM; all other
CYPs > 30 M) once again precluded further advancement.
Similar CYP issues plagued 17d as well, despite good CNS
penetration (Kp = 2.2). The carbon-linked pyrazole 17e was
attractive in terms of PAM activity (EC50 = 45 nM, 92% Glu
Max), low predicted hepatic clearance (CLhep of 11.5 and 21.9
mL/min/kg for human and rat, respectively), good plasma
protein binding (fus 0.096 and 0.088 for rat and human,
respectively) and excellent CNS penetration in rat (Kp = 1.6);
however, inhibition of CYPs 1A2 and 3A4 halted progression.
As shown in Table 1, a number of analogs 15 displayed
attractive mGlu4 PAM potencies and efficacies (EC50s as low
as 64 nM and with % GluMax up to 277%). A variety of
tertiary amines (15a, 15f) and lipophilic amines (15h, 15i) were
well tolerated, as were some secondary amines (15d, 15g).
Table 1. Structures and human activities for mGlu4 PAM analogs 15.
NR1R2
N
N
HN
N
H
N
15
hmGlu4
% Glu Maxa
184
Cpd
NR1R2
EC50 (nM)a
15a
215
N
Me
N
15b
1,290
219
N
N
15c
15d
15e
200
71
1,900
868
H
N
H
H
N
N
145
217
174
Table 2. Structures and human activities for mGlu4 PAM analogs 17.
1,350
164
N
R
15f
15g
15h
N
N
HN
OMe
120
305
249
N
H
N
135
277
N
CF3
F
17
F
15i
hmGlu4
EC50 (nM)a
% Glu Maxa
Cpd
R
N
17a
17b
17c
17d
17e
90
98
15j
N
N
45
71
8.3
42
45
96
N
63.4
237
15k
F
F
100
N
99
F3C
15l
104
N
98
726
N
N
N
aFor SAR determination, calcium mobilization human mGlu4/Gqi5
assays were performed n = 1 independent times in triplicate with an
EC20 fixed concentration of glutamate.
92
F3C
17f
N
N
132
98
aFor SAR determination, calcium mobilization human mGlu4/Gqi5
assays were performed n = 1 independent times in triplicate with an
EC20 fixed concentration of glutamate.
However, these analogs showed high predicted hepatic
clearance (CLhep >19 and >60 mL/min/kg for human and rat,
respectively), poor CYP450 profiles (IC50’s <2 M at one or
more CYPs) and high plasma protein binding.
Of these
We next explored disubstitution of the isoquinoline core, as
with PAMs 18 and 19 (Figure 4). Halogen substitution in the
3-position, as with 18, led to a 10- to 20-fold loss in mGlu4
PAM potency and lower fraction unbound, but with improved
predicted hepatic clearance and CNS penetration (Kps >3).
Additional substitution at the 4-position (analogs 19) resulted
in maintained potent mGlu4 PAM activity and CNS penetration
(Kps >3), but CYP1A2 inhibition uniformly was less than 500
nM, once again stopping this series from advancement.
derivatives, the N-linked pyrazole analog 15j was the most
promising (EC50 = 63.4 nM, 96.1% Glu Max). Moreover, 15j
showed moderate predicted hepatic clearance (CLhep of 14.3
and 36.3 mL/min/kg for human and rat, respectively), with an
improved CYP450 profile relative to 12b (1A2 IC50 = 1.5 M,
2C9 IC50 = 7.3 M, 2D6 IC50 = 7.2 M, 3A4 IC50 = 13 M)
and good fraction unbound in rat and human plasma (fus of
0.032 and 0.030, respectively). Moreover, PAM 15j was CNS
penetrant (Kp = 1.37), and displayed a robust IVIVC (rat CLp =
35.7 mL/min/kg); however, its in vivo half-life was less than 30
minutes, which precluded further advancement.

R
R
aReagents and conditions: (a) (CF3CO)2O, CH2Cl2, Et3N, rt, 1 h, 87%; (b) i) 2-
chloropyridine, CH2Cl2, -78 °C, then Tf2O, ii) wave, 160 °C, 5 min, 56%; (c)
MnO2, xylene, 130 °C, 18 h, 44%; (d) 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-
b]pyridine-3-amine or 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazine-3-
amine or 1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine-3-amine, 5 mol%
Pd2(dba)3, 5 mol% XantPhos, Cs2CO3, 1,4-dioxane, µwave, 140 °C, 30 min,
65-72%; (g) TFA, toluene, 100 °C, 30 min, 80-86%.
N
N
N
N
HN
HN
N
Cl, F
N
H
H
Cl, F
N
N
18
19
Aromatization with MnO2 in refluxing xylene afforded CF3
isoquinoline 24. As we wanted to evaluate the CF3
isoquinoline in the context of several different mGlu4 PAM
warheads, 24 was subjected to a Buchwald coupling with
varied 3-amino-aza-indazoles to give after TFA deprotection,
25a, 25b and 25c, respectively. While 25a and 25b were potent
mGlu4 PAMs (Table 4), both suffered from potent CYP1A2
Figure 4. Structures of disubstituted analogs 18 and 19.
In an attempt to mitigate the CYP1A2 inhibition, we
explored a series of isoquinolinones 20. As shown in Table 3,
the unsubstituted isoquinolinone 20a was a moderately potent
mGlu4 PAM (EC50 = 464 nM, 83% Glu Max) with moderate
predicted hepatic clearance (CLhep 13.4 and 49.6 mL/min/kg
for human and rat, respectively) and with an acceptable CYP450
profile (1A2 IC50 = 3.3 M, 2C9, 2D6 and 3A4 IC50s >30 M).
Unfortunately, the inclusion of an additional hydrogen-bond
donor/acceptor led to no detectable CNS exposure in rats.
Alkylation to afford analogs 20b-e, led to a loss in mGlu4 PAM
potency and efficacy, forcing the team to abandon the
isoquinolinone core.
Table 4. Structures and human activities for mGlu4 PAM analogs 25.
CF3
N
N
HN
N
W
H
X
25
Table 3. Structures and human activities for mGlu4 PAM analogs 20.
b
X
hmGlu4
% Glu Maxa
Rat Kp
Cpd
W
O
R
EC50 (nM)a
17.8
N
N
CH
N
N
N
4.34
ND
HN
25a
25b
94.4
97.6
92.6
N
H
41.1
64.6
N
20
N
CH
1.51
25c
aFor SAR determination, calcium mobilization human mGlu4/Gqi5 assays were
performed n = 1 independent times in triplicate with an EC20 fixed
concentration of glutamate. bTotal brain:plasma partition coefficients
determined at 0.25 h post-administration of an IV cassette dose
(0.20–0.25 mg/kg) to male, SD rats (n = 1); ND = not determined
hmGlu4
% Glu Maxa
Cpd
R
H
EC50 (nM)a
20a
20b
20c
83
44
464
CH3
>10,000
685
inhibition (IC50s <500 nM), poor in vivo rat PK (t1/2s <1 hr) and
modest efficacy in our HIC model (~24% reversal at 3 mg/kg
PO), highlighting the impact of subtle aza-modifications to the
overall system. Interestingly, 25c, while not the most potent
analog, possessed a balanced profile worthy of advancement.
PAM 25c was potent (hmGlu4/Gqi5 EC50 = 64.6 nM, pEC50 =
7.19 ± 0.14, 92.6 ± 5.0% Glu Max, rat mGlu4/GIRK: EC50=197
nM pEC50=6.71±0.17, Glu Max=123.2±1.1% Max), with low
predicted hepatic clearance (CLhep 9.0 and 0 mL/min/kg for
human and rat, respectively) and excellent CNS penetration (Kp
= 1.51). In the HIC model, 25c afforded an ~50% reversal at 3
mg/kg PO, and a minimum effective dose (MED) of 1 mg/kg
PO. As recently described,16 25c showed excellent
pharmacokinetics across species (low CLps, %F > 35%), an
acceptable CYP profile (>30 M vs. 3A4, 2D6 and 2C9, 12.5
M vs. 2C19 and 1.5 M vs. 1A2), no CYP induction or time-
dependent inhibition and excellent metabolite coverage across
species. PAM 25c also afforded attractive predicted human PK
parameters (CLps 5-9 mL/min/kg, Vds 1-2 L/kg and t1/2 2-4
hours). Finally, an enabling spray-dried dispersion formulation
(25:75 25c:HPMCP-HPSS SDD) facilitated dose escalation in
rat and non-human primate.18
40
51
36
20d
20e
653
1,725
aFor SAR determination, calcium mobilization human mGlu4/Gqi5
assays were performed n = 1 independent times in triplicate with an
EC20 fixed concentration of glutamate.
We rationalized that the 1-CF3 moiety might provide the
‘right’ balance of properties to advance towards a preclinical
development candidate. To install the CF3 group, we needed
a revised synthetic plan (Scheme 3).18
Acylation of
commercially available amine 21 provided 22. A Bischler-
Napieralski reaction then delivered imine 23 in modest yield.
Scheme 2. Synthesis of mGlu4 PAMs analogs 25.a
O
CF3
b
a
HN
CF3
NH2
N
Br
Br
Br
21
22
23
In conclusion, we have detailed, for the first time, the
optimization campaign from VU0418506 (4) to the -CF3
isoquinoline-based 25c (VU2957, Valiglurax), an mGlu4 PAM
preclinical development candidate. Along the way, variable
CYP inhibition profiles, especially with respect to CYP1A2,
and challenges with CNS penetration were overcome to deliver
a pre-clinical development candidate with a balanced profile,
affording robust oral efficacy in our pharmacodynamic model
CF3
N
CF3
N
N
HN
d,e
c
N
W
H
Br
X
W, X = CH, N
24
25

(HIC) and acceptable human PK predictions.
Further
progression of 25c, as well as back-up series, will be reported
in due course.
Acknowledgments
We thank William K. Warren, Jr. and the William K. Warren
Foundation who funded the William K. Warren, Jr. Chair in
Medicine (to C.W.L.).
References
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(2) Robichaud AJ, Engers DW, Lindsley CW, et al. ACS Chem. Neurosci.
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HIGHLIGHTS



First description of the SAR that led to the
discovery of VU2957 (Valiglurax)
Valiglurax is only the second mGLu4 PAM
clinical candidate for Parkinson’s disease
The new series afford improvements in
protein binding, half-life in vivo, CNS
penetration and oral bioavailability.
Highlights subtle differences in

positioning of hydrogen-bond acceptors
and impact on CNS penetration/P-gp
liability.