Lead optimization of the VU0486321 series of mGlu1PAMs. Part 2: SAR of alternative 3-methyl heterocycles and progress towards an in vivo tool

Article abstract of DOI:10.1016/j.bmcl.2015.12.104

This Letter describes the further lead optimization of the VU0486321 series of mGlu₁positive allosteric modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep and caveat-laden SAR plagues the series, but ultimately potent mGlu₁PAMs (EC₅₀s ～5 nM) have resulted with good DMPK properties (low intrinsic clearance, clean CYP profile, modest F_u) and CNS penetration (K_ps 0.25-0.97), along with up to >450-fold selectivity versus mGlu₄and mGlu₅.

Full text of DOI:10.1016/j.bmcl.2015.12.104

Bioorganic & Medicinal Chemistry Letters 26 (2016) 751–756
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 2:
SAR of alternative 3-methyl heterocycles and progress towards
an in vivo tool
Pedro M. Garcia-Barrantes a, Hyekyung P. Cho a,b, Adam M. Metts c, Anna L. Blobaum a,
Colleen M. Niswender a,b, P. Jeffrey Conn a,b, Craig W. Lindsley a,b,c,
⇑
a Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
b Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
c Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric
modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep
and caveat-laden SAR plagues the series, but ultimately potent mGlu1 PAMs (EC50s ꢀ5 nM) have resulted
with good DMPK properties (low intrinsic clearance, clean CYP profile, modest Fu) and CNS penetration
(Kps 0.25–0.97), along with up to >450-fold selectivity versus mGlu4 and mGlu5.
Received 15 December 2015
Accepted 30 December 2015
Available online 2 January 2016
Keywords:
mGlu1
Ó 2016 Elsevier Ltd. All rights reserved.
Metabotropic glutamate receptor
Positive allosteric modulator (PAM)
Schizophrenia
Structure–Activity Relationship (SAR)
Driven by the recent reports of deleterious non-synonymous
single nucleotide polymorphisms (nsSNPS) in the GRM1 gene,
which encodes the metabotropic glutamate receptor subtype 1
(mGlu1), that correlated with a higher incidence of neuropsychi-
atric disease,1–3 interest in mGlu1 PAMs has increased.3 In vitro,
we have shown that mGlu1 PAMs can potentiate, and in some cases
restore activity to wild-type levels in these mutants.3 However,
historical tools lacked the DMPK profiles to serve as robust
in vivo tools.3–6 En route to the ideal in vivo tool, our lab has pub-
lished many advancements in the mGlu1 PAM ligand field,3,5,6 as
well as demonstrating that the adverse effect of epileptiform dis-
charges and seizure liability of Group I mGluR agonists, such as
DHPG, is not mGlu1 mediated,5 and therefore widening the thera-
peutic window for mGlu1 PAMs (Fig. 1).
As previously discussed, our entry into the VU0486321 (4) ser-
ies of mGlu1 PAMs was via a ‘double molecular switch’ of an mGlu4
PAM ligand.3,7,8 While surveying a diverse array of five-membered
heterocyclic amides in the optimization effort, only a furyl amide
was active, but substitution with a 3-methyl group, as in 4 and 5,
greatly enhanced mGlu1 PAM potency.5,6 However, we never went
back and surveyed the impact of incorporation of a methyl moiety
in the context of other five-membered heterocycles, with more
desirable physiochemical and DMPK properties than a furyl ring
(Fig. 2). In this Letter, we will detail the steep and caveat-laden
SAR en route to an in vivo tool compound within the VU0486321
(4) series of mGlu1 PAMs.
In order to access analogs 6 and survey the SAR for the three
regions highlighted in Figure 2, a general three step synthetic route
was developed. As shown in Scheme 1, commercial, functionalized
p-amino nitroarenes/heteroarenes 7 were condensed with various
phthalic anhydrides to afford analogs 8. The nitro group was
reduced to the aniline 9 via hydrogenation conditions, and final
analogs 6 were afforded by standard amide coupling conditions
with a diverse array of 3-methyl substituted five-membered
heterocyclic acids.
For the initial library to survey alternative, five-membered
heterocyclic amides with a methyl group adjacent to the amide,
we employed an unsubstituted phthalimide moiety and held the
3-chlorophenyl moiety constant. As shown in Table 1, this library
afforded active mGlu1 PAMs, and further highlights the impact of
a methyl substituent (as des-methyl congeners were all inactive,
EC50s > 10
regioisomeric congeners displayed divergent SAR. In case of
l
M).6 However, not all analogs 10 were active, and even
⇑
Corresponding author.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
http://dx.doi.org/10.1016/j.bmcl.2015.12.104
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.

752
P. M. Garcia-Barrantes et al. / Bioorg. Med. Chem. Lett. 26 (2016) 751–756
Cl
O
Cl
O
O
N
H
N
O
N
N
N
H
N
O
N
F3C
N
H
O
O
NO2
Cl
2
3, VU0483605
hmGlu1 PAM (EC50 = 390 nM)
1
, VU-71
, Ro 07-11401
µ
>10 M versus mGlu4
F
O Cl
O
O
O
F
O
O
N
NH
N
NH
O
O
4, VU0486321
hmGlu1 EC50 = 31.8 nM (98%)
improved PK, Kp, plasma stability
5, VU6002194
hmGlu1 EC50 = 12.9 nM (84%)
>793-fold selective vs. mGlu4
~35-fold selective vs. mGlu4
Figure 1. Structures of representative mGlu1 PAMs 1–5.
iterative
parallel
F
R2
O
Cl
O
R1
O
O
O
W
Z
X
Y
N
NH
synthesis
N
NH
O
O
4, VU0486321
6
Figure 2. Chemical optimization plan to access multi-dimensional SAR around analogs 6.
tiomeric, N-methyl prolines 10l and 10m, were inactive. These
were very exciting findings overall, especially in the case of 10i, a
56 nM mGlu1 PAM, where a single methyl group increased potency
almost 200-fold relative to the unsubstituted thiazole.6 These data
narrowed down the field to four methyl-substituted heterocycles
(10g, 10i, 10j and 10k) for further optimization in the context of
functionalized phthalimides, and determine if SAR developed
within the 3-furylamide series (4 and 5) would translate.
Next, we prepared a 4 Â 7 matrix library to assess SAR of the
four methyl-substituted heterocycles (10g, 10i, 10j and 10k) in
the context of seven differentially substituted (3-Me, 4-Me, 3-Cl,
4-Cl, 3-F, 4-F and 4-aza) phthalimide moieties (Table 2) to provide
analogs 11. As mGlu4 has been a pervasive anti-target, we also
counter-screened the 28-membered library against mGlu4, in
singlicate, to understand any undesired off-target activity.
R1
R1
O
R2
a
b
N
NO2
H2N
NO2
O
7
8
R1
R1
O
O
N
O
O
W
Z
R2
R2
X
Y
c
N
NH2
NH
O
9
6
Scheme 1. Reagents and conditions: (a) phthalic anhydrides, AcOH, reflux, 53–94%;
(b) H2, Pd/C, EtOH, rt, 94–99%; (c) methyl substituted five-membered heterocyclic
acids, HATU, DCM, rt, 39–98%.
While the SAR was steep amongst the imidazole (11o–u) and
pyrazole (11v–bb) congeners, the oxazole (11a–g) and thiazole
(11h–n) uniformly provided potent mGlu1 PAMs (EC50s down to
22 nM) with
a dynamic range of selectivity versus mGlu4
regioisomeric thiophenes, both 10d and 10e were equipotent, but
weak mGlu1 PAMs (EC50s 1.5–1.8 lM); however, both oxadiazoles
(10f and 10g) and thiazoles (10h and 10i) displayed divergent SAR,
with the 5-methyl regioisomers 10g and 10i displaying potent
(from 0.7- to >52-fold). This lack of mGlu4 selectivity was not
unexpected based on the central Cl-phenyl core from earlier SAR
efforts. However, we were pleased to see that thiazoles and oxa-
zoles could effectively replace the furyl moiety, even those analogs
11 could not advance as in vivo tools. Previously, we demonstrated
that replacement of the Cl-phenyl core as in 4 and analogs 11, with
a fluorine atom in the 3-position (relative to the phthalimide moi-
ety, as in 5) maintained mGlu1 PAM potency, while eliminating
PAM activity (EC50s of 1.47
the 4-methyl regioisomers 10f and 10h were inactive
(EC50s > 10 M). An imidazole analog 10j was also active
(EC50 = 374 nM), but strongly basic amines, such as the two enan-
lM and 56 nM, respectively), while
l

P. M. Garcia-Barrantes et al. / Bioorg. Med. Chem. Lett. 26 (2016) 751–756
753
Table 1
Structures and activities for analogs 10
O
Cl
O
W
Z
X
Y
N
NH
O
Het
10
Compd
Het
hmGlu1
mGlu1 pEC50
( SEM)
EC50
(l
M)a
[% Glu Max SEM]
3.42
[95 8]
H
N
10a
5.46 0.13
>10
[À]
10b
10c
10d
10e
10f
>5
NH
5.26
[95 4]
5.28 0.10
5.72 0.27
5.82 0.17
>5
N
1.89
[105 11]
S
1.51 [105 8]
S
>10
[À]
O
N
1.47
[100 17]
N
10g
5.83 0.02
O
>10
[À]
S
10h
10i
>5
N
0.056
[96 7]
N
7.23 0.13
6.45 0.13
5.91 0.21
S
0.374
[59 1]
N
10j
N
H
N
1.24
[107 11]
N
10k
>10
[À]
10l
>5
>5
N
>10
[À]
10m
N
a
Calcium mobilization mGlu1 assays, values are average of three (n = 3) independent experiments performed in triplicate.
mGlu4 activity (>793-fold selective).6 Therefore, we synthesized
analogs of 11a–n to survey the impact of the regioisomer fluorine
core (analogs 12, Table 3) in a 10 lM single-point assay prior to
running full CRCs. Surprisingly, none of these analogs were strong
active mGlu1 PAMs (<50% potentiation of EC20 glutamate at
10 lM), highlighting once again the steep SAR challenges with
allosteric ligands. Thus, it was clear that the more basic thiazole
analogs could not be advanced due to the lack of selectivity versus
mGlu4, and that the SAR developed to abolish activity at mGlu4 did
not translate to the thiazoles.
The highly potent and selective mGlu1 PAM 5, was only prepared
and evaluated in the context of an unsubstituted phthalimide moi-
ety; therefore, it seemed prudent to further explore functionalized
phthalimide analogs of 5, and assess physiochemical properties
and selectivity in hopes of developing a robust in vivo tool com-
pound. Following the route outlined in Scheme 1, we synthesized
five functionalized analogs 13a–e (Table 4). Unlike the oxazole
and thiazole congeners 12, the furyl analogs 13 proved to be very
potent mGlu1 PAMs (EC50
s 5.3–25.7 nM), and both electron
donating and electron withdrawing substituents were tolerated.

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P. M. Garcia-Barrantes et al. / Bioorg. Med. Chem. Lett. 26 (2016) 751–756
Table 2
Structures and activities for analogs 11
O Cl
N
O
R1
W
Z
X
Y
NH
O
Het
11
Compd
R1
Het
hmGlu1
mGlu1
pEC50
( SEM)
hmGlu4
Fold versus mGlu4
EC50
(l
M)a
EC50 (lM)
[% Glu Max SEM]
[% Glu Maxb]
0.041
[98 2]
0.198
[75]
N
11a
11b
11c
11d
11e
11f
3-Me
4-Me
3-Cl
4-Cl
3-F
7.38 0.11
6.32 0.13
7.26 0.13
5.88 0.26
6.85 0.09
5.77 0.18
5.77 0.18
7.66 0.12
6.64 0.14
7.30 0.15
5.86 0.28
7.20 0.14
6.73 0.16
4.8
O
0.469
[91 5]
0.519
[39]
N
0.9
O
0.054
[104 4]
0.405
[67]
N
7.4
O
1.29
[112 15]
0.983
[24]
N
0.7
O
0.141
[93 3]
0.642
[36]
N
4.6
O
0.241
[98 7]
>10
[À]
N
4-F
1.7
O
1.70
[91 8]
2.53
[45]
N
11g
11h
11i
4-Aza
3-Me
4-Me
3-Cl
4-Cl
3-F
>5.9
51.1
6.1
O
0.022
[86 2]
1.12
[161]
N
S
0.232
[104 5]
1.41
[75]
N
S
0.051
[91 3]
1.98
[169]
N
11j
39.1
>7.3
4.9
S
1.37
[121 12]
>10
[59]
N
11k
11l
S
S
0.063
[98 4]
0.306
[52]
N
0.187
[111 6]
0.474
[52]
N
11m
4-F
2.5
S
0.191
[98 4]
>10
[À]
N
11n
4-Aza
6.72 0.11
>52
S
N
0.254
[108 8]
0.602
[124]
11o
11p
3-Me
4-Me
6.60 0.20
>5
2.4
—
N
N
>10
0.506
[32]
N
N
[30 1]
N
N
0.265
[103 5]
1.573
[145]
11q
11r
11s
3-Cl
4-Cl
3-F
6.58 0.13
>5
5.9
—
>10
[30 1]
>10
[30]
N
N
N
0.673
6.17 0.12
1.07
[63]
1.5
[87 4]

P. M. Garcia-Barrantes et al. / Bioorg. Med. Chem. Lett. 26 (2016) 751–756
755
Table 2 (continued)
Compd
R1
Het
hmGlu1
EC50
M)a
[% Glu Max SEM]
mGlu1
pEC50
( SEM)
hmGlu4
Fold versus mGlu4
(l
EC50 (lM)
[% Glu Maxb]
N
>10
[43 9]
1.09
[42]
11t
4-F
>5
>5
—
—
N
N
>10
[44 8]
>10
[À]
11u
4-Aza
N
H
N
0.557
[106 7]
2.75
[133]
N
N
N
N
N
11v
11w
11x
11y
11z
3-Me
4-Me
3-Cl
4-Cl
3-F
6.25 0.16
5.36 0.22
6.07 0.09
>5
4.9
>2
3.9
—
H
N
4.94
[110 15]
>10
[À]
H
N
0.855
[113 5]
3.38
[117]
H
N
>10
[94 2]
>10
[À]
H
N
0.632
[106 5]
6.20
[59]
6.20 0.17
9.8
H
N
0.599
[83 6]
>10
[À]
N
11aa
4-F
7.65 0.13
>5
>16
—
H
>10
[37 9]
>10
[27]
N
N
11bb
4-Aza
a
Calcium mobilization mGlu1 assays, values are average of three (n = 3) independent experiments performed in triplicate.
Glu Max is expressed as % of PHCCC response.
b
Table 3
Structures and activities for analogs 12
O
F
O
N
R1
X
N
NH
O
12
Compd
R1
X
% Glu Max (10
l
M)a
Compd
R1
X
% Glu Max (10 l
M)a
12a
12b
12c
12d
12e
12f
H
O
O
O
O
O
O
O
O
18
14
20
25
27
16
36
9
12i
12j
H
S
S
S
S
S
S
S
S
45
36
17
40
22
45
43
42
3-Me
4-Me
3-Cl
4-Cl
3-F
3-Me
4-Me
3-Cl
4-Cl
3-F
12k
12l
12m
12n
12o
12p
12g
12h
4-F
4-Aza
4-F
4-Aza
a
Calcium mobilization mGlu1 assays, single point at 10 lM.
As these new analogs 13 were equipotent or more potent than 5, we
assessed their disposition in a battery of in vitro and in vivo DMPK
assays (Table 5).9 All of the analogs displayed excellent CYP profiles
noted previously due hydrolysis of the phthalimide).5 However,
the compounds were stable in human plasma, as well as rat brain
homogenate, and importantly, in vivo. Analogs 13 were also CNS
penetrant, with Kps of 0.25–0.95 in rat PBL cassette studies. There-
fore, all of these new analogs 13 were attractive and were potential
in vivo mGlu1 PAM tools compounds. In vivo rat PK after IV admin-
istration showed a wide range of clearance values (4.61 mL/min/kg
to 65.5 mL/min/kg) and a disconnection from the in vitro predicted
values (e.g., lack of IVIVC). Especially in the case of compounds 13a
and 13b, were clearance was, respectively, 8 and 4 times lower than
the in vitro predicted value. It was also interesting to find a more
(most IC50s > 30 lM against 3A4, 2C9, 2D6 and 1A2), low to moder-
ate hepatic clearance in both rat (28.9 mL/min/kg to 52 mL/min/kg)
and human (4.4 mL/min/kg to 11.9 mL/min/kg) microsomal incuba-
tions and exceptional free fraction in rat brain homogenate binding
studies (Fu0.034–0.29), the latter suggesting high free drug levels in
the CNS. Analogs 13 displayed high protein binding in both rat and
human plasma (rapid equilibrium dialysis binding assay), and low
recovery suggested modest instability in rat plasma in vitro (as

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P. M. Garcia-Barrantes et al. / Bioorg. Med. Chem. Lett. 26 (2016) 751–756
Table 4
(>450 to>2000-fold selective) against both mGlu4 and mGlu5 (EC50
-
Structures and activities for analogs 13
s >>10 M). Thus, potent, selective and CNS penetrant mGlu1 PAMs
l
were developed.
O
F
O
O
R1
In conclusion, the continued optimization of the VU0486321
series of mGlu1 PAMs has provided unique SAR, and highlighted
the critical value of a single methyl group, a ‘magic methyl’ effect
to engender PAM activity across a broad array of 5-member hete-
rocycles. While we encountered instances of robust SAR, the clas-
sical steep SAR of allosteric modulators was noted, with key
mGluR selectivity handles not translating to structurally similar
chemotypes. However, revisiting the furyl amide congeners in
the context of functionalized phthalimides, led to a sub-series of
highly potent and CNS penetrant (Kps of 0.25–0.95) mGlu1 PAMs,
with favorable DMPK profiles (low CLp, t1/2s up to 4.9 h and desir-
able volumes of distribution) and excellent selectivity profiles ver-
N
O
NH
13
Compd R1
hmGlu1 EC50 (nM)a [% Glu Max SEM] mGlu1 pEC50 ( SEM)
13a
13b
13c
13d
13e
3-Me 11.4
[81 2]
4-Me 25.7
7.94 0.05
7.59 0.04
8.27 0.02
7.71 0.06
7.65 0.07
[70 2]
5.3
[60 2]
19.3
[81 2]
22.0
3-Cl
3-F
4-F
sus mGlu4 and mGlu5 (EC50s >>10 lM, >450- to >2000-fold
selective). Of these, VU6004909 (13b) emerged as a near ideal
rodent in vivo tool compound to probe selective mGlu1 activation.
[67 2]
a
Calcium mobilization mGlu1 assays, values are average of three (n = 3) inde-
Acknowledgments
pendent experiments performed in triplicate.
We thank William K. Warren, Jr. and the William K. Warren
Foundation who funded the William K. Warren, Jr. Chair in Medi-
cine (to C.W.L.). P.M.G. would like to acknowledge the VISP pro-
gram for its support. This work was funded by the William K.
Warren, Jr. Chair in Medicine and the NIH (U54MH084659).
Table 5
DMPK characterization of mGlu1 PAMs 13a–e
Parameter
13a
13b
13c
13d
13e
Hum CLhep (ml/min/kg) 4.40
6.64
28.9
0.009
0.038
0.298
11.9
46.7
<0.001
0.001
0.272
6.72
52.0
0.03
0.011
0.17
4.48
35.8
0.027
0.011
0.034
Rat CLhep (ml/min/kg)
Hum Fu plasma
Rat Fu plasmaa
Rat Fu brain
35.0
References and notes
0.002
0.009
0.193
1. Frank, R. A. W.; McRae, A. F.; Pocklington, A. J.; van de Lagemaat, L. N.; Navarro,
P.; Croning, M. D. R.; Komiyama, N. H.; Bradley, S. J.; Challiss, R. A. J.; Armstrong,
J. D.; Finn, R. D.; Malloy, M. P.; MacLean, A. W.; Harris, S. E.; Starr, J. M.; Bhaskar,
S. S.; Howard, E. K.; Hunt, S. E.; Coffey, A. J.; Raganath, V.; Deloukas, P.; Rogers, J.;
Muir, W. J.; Deary, I. J.; Blackwood, D. H.; Visscher, P. M.; Grant, S. G. N. PLoS One
2011, 6, e19011.
2. Ayoub, M. A.; Angelicheva, D.; Vile, D.; Chandler, D.; Morar, B.; Cavanaugh, J. A.;
Visscher, P. M.; Jablensky, A.; Pfleger, K. D. G.; Kalaydijeva, L. PLoS One 2012, 7,
e32849.
3. Cho, H. P.; Garcia-Barrantes, P. M.; Brogan, J. T.; Hopkins, C. R.; Niswender, C. M.;
Rodriguez, A. L.; Venable, D.; Morrison, R. D.; Bubser, M.; Daniels, J. S.; Jones, C.
K.; Conn, P. J.; Lindsley, C. W. ACS Chem. Biol. 2014, 9, 2334.
4. Vieira, E.; Huwyler, J.; Jolidon, S.; Knoflach, F.; Mutel, V.; Wichmann, J. Bioorg.
Med. Chem. Lett. 2009, 19, 1666.
5. Garcia-Barrantes, P. M.; Cho, H. P.; Niswender, C. M.; Byers, F. W.; Locuson, C.
W.; Blobaum, A. L.; Xiang, Z.; Rook, J. M.; Conn, P. J.; Lindsley, C. W. J. Med. Chem.
2015, 58, 7959.
CYP450 IC50
1A2 2C9
2D6 3A4
(lM)
10 >30
>30 >30 6.3 >30
>30 >30 >30 >30
>30 >30 >30 >30 >30 >30 >30 >30 >30 >30
Rat iv PK (0.25 mg/kg)
t1/2 (min)
296
330
4.61
1.52
285
186
6.94
1.29
51.5
45.4
65.5
2.97
38.9
30.7
62.6
1.92
76.6
80.4
16.7
1.34
MRT (min)
Clp (mL minÀ1 kgÀ1
)
Vss (L/kg)
Rat iv PBL (0.25 mg/kg)
Cn plasma (ng/mL)
Cn brain (ng/g)
699
177
0.25
191
182
0.95
217
120
0.55
0.97
147
0.95
151
97.2
0.64
Kp (at 0.25 h)
a
Indicates moderate compound instability in rat plasma in vitro.
6. Garcia-Barrantes, P. M.; Cho, H. P.; Niswender, C. M.; Blobaum, A. L.; Conn, P. J.;
Lindsley, C. W. Bioorg. Med. Chem. Lett. 2015, 25, 5107.
7. Jones, C. K.; Engers, D. W.; Thompson, A. D.; Field, J. R.; Blobaum, A. L.; Lindsley,
S. R.; Zhou, Y.; Gogliotti, R. D.; Jadhav, S.; Zamorano, R.; Daniels, J. S.; Morrison,
R.; Weaver, C. D.; Conn, P. J.; Lindsley, C. W.; Niswender, C. M.; Hopkins, C. R. J.
Med. Chem. 2011, 54, 7639.
8. Wood, M. R.; Hopkins, C. R.; Brogan, J. T.; Conn, P. J.; Lindsley, C. W. Biochemistry
2011, 50, 2403.
9. Gentry, P. R.; Kokubo, M.; Bridges, T. M.; Byun, N.; Cho, H. P.; Smith, E.; Hodder,
P. S.; Niswender, C. M.; Daniels, J. S.; Conn, P. J.; Lindsley, C. W.; Wood, M. R. J.
Med. Chem. 2014, 57, 7804.
rational trend in the in vivo clearance, where the electronic charac-
ter and the position of the substituents on the phthalimide moiety
impacts the disposition of the compounds. From this study, com-
pound 13b emerged as the mGlu1 PAM with the best pharmacoki-
netic profile to date (CLp = 6.94 mL/min/kg, t1/2 = 4.75 h, Vss
=
1.29 K/kg) and with high CNS penetration (Kp = 0.95). Finally, we
assessed selectivity versus mGlu4 and mGlu5, key anti-targets for
this chemotype and found 13a–13e were all uniformly inactive