Discovery of Novel Central Nervous System Penetrant Metabotropic Glutamate Receptor Subtype 2 (mGlu2) Negative Allosteric Modulators (NAMs) Based on Functionalized Pyrazolo[1,5- a]pyrimidine-5-carboxamide and Thieno[3,2- b]pyridine-5-carboxamide Cores

Article abstract of DOI:10.1021/acs.jmedchem.8b01266

A scaffold hopping exercise from a monocyclic mGlu₂ NAM with poor rodent PK led to two novel heterobicyclic series of mGlu₂ NAMs based on either a functionalized pyrazolo[1,5-a]pyrimidine-5-carboxamide core or a thieno[3,2-b]pyridine-5-carboxamide core. These novel analogues possess enhanced rodent PK, while also maintaining good mGlu₂ NAM potency, selectivity (versus mGlu₃ and the remaining six mGlu receptors), and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.

Full text of DOI:10.1021/acs.jmedchem.8b01266

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Brief Article
Discovery of novel central nervous system penetrant metabotropic
2
glutamate receptor subtype 2 (mGlu) Negative Allosteric Modulators
(NAMs) based on functionalized pyrazolo[1,5-a]pyrimidine-5-
carboxamide and thieno[3,2-b]pyridine-5-carboxamide cores
Elizabeth S Childress, Joshua M. Wieting, Andrew S Felts, Megan M Breiner, Madeline
F Long, Vincent B Luscombe, Alice L Rodriguez, Hyekyung P. Cho, Anna L. Blobaum,
Colleen M Niswender, Kyle A Emmitte, P. Jeffrey Conn, and Craig W Lindsley
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b01266 • Publication Date (Web): 23 Oct 2018
Downloaded from http://pubs.acs.org on October 24, 2018
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Discovery of novel central nervous system penetrant metabotropic
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glutamate receptor subtype 2 (mGlu ) Negative Allosteric
2
Modulators (NAMs) based on functionalized pyrazolo[1,5-
a]pyrimidine-5-carboxamide and thieno[3,2-b]pyridine-5-
carboxamide cores
Elizabeth S. Childress,§,‡ Joshua M. Wieting, Andrew S. Felts, Megan M. Breiner, Madeline F. Long, §,‡ Vincent B.
§,‡
§,‡
§,‡
Luscombe,§,‡ Alice L. Rodriguez,§,‡ Hyekyung P. Cho , Anna L. Blobaum, Colleen M. Niswender, §,‡,# Kyle A.
Emmitte,§,‡, ψ P. Jeffrey Conn, §,‡,# Craig W. Lindsley*§,‡,ψ
§,‡
§,‡
§
‡
ψ
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Department of Chemistry, Vanderbilt
#
University, Nashville, Tennessee 37232 Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville,
TN 37232,
2
KEYWORDS. Negative allosteric modulator (NAM), metabotropic glutamate receptor 2 (mGlu ), CNS penetration, structure-activity-relationship (SAR)
Supporting Information Placeholder
ABSTRACT: A scaffold hopping exercise from a monocyclic mGlu
mGlu NAMs based on either a functionalized pyrazolo[1,5-a]pyrimidine-5-carboxamide core or a thieno[3,2-b]pyridine-5-carboxamide
core. These novel analogs possess enhanced rodent PK, while also maintaining good mGlu NAM potency, selectivity (versus mGlu and
the remaining six mGlu receptors) and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.
2
NAM with poor rodent PK led to two novel heterobicyclic series of
2
2
3
INTRODUCTION
NAM pharamacophore, and identified 4, a potent (IC50 = 78 nM,
cLogP = 1.90), selective (>30 M versus mGlu1,3-8) and highly CNS
The presynaptic Group II metabotropic glutamate receptors (mGlu
and mGlu ) are broadly expressed in the CNS and represent important
3
2
2
4
p 2
penetrant (K = 1.9) mGlu NAM. While this was an advancement,
the very high plasma clearance
therapeutic targets for a number of CNS disorders (e.g., anxiety,
depression, schizophrenia, pain, addiction, Alzheimer’s disease
(
(
AD), and Parkinson’s disease (PD)).1-14 Early proof-of-concept
POC) studies were performed with dual orthosteric mGlu2/3
antagonists, agonists or PAMs (positive allosteric modulators), and
thus the physiological and therapeutic roles of the individual subtypes
was unclear.9-13 More recently, highly selective mGlu
mGlu NAMs have emerged with properties suitable for in vivo POC
studies.14-20 Lilly has developed a highly selective orthosteric mGlu
agonist, but no mGlu PAMs have been reported in the literature to
date.21 Progress has been made in the development of mGlu
NAMs
Figure 1), and are represented by 1-4. First generation mGlu NAM
ligands (e.g., 1-3) are characterized by either poor physiochemical
properties (e.g., high lipophilicity, low f and poor solubility), rapid
disposition (very high plasma clearance (CL ) and short half-life
1/2)) and/or very low CNS penetration (rat brain:plasma partition
ratios, or K
s of ≤0.3).22-25 In an attempt to address these limitations,
we adopted a reductionist optimization strategy to simplify the mGlu
PAMs and
2
3
3
3
2
(
2
u
p
(t
p
2
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N
O
O
O
O
F
O
N
O
HO
N
N
O
O
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
N
N
O
Br
NH2
N
NH2
O
CH3
N
N
N
O
N
O
R1
R1
R1
a
R1
b
c
R2
R2
R2
R2
OCH3
F
7
8
9
10
1
2
O
O
O
mGlu2 IC50 = 146 nM
mGlu2 IC50 = 207 nM
mGlu3 IC50
>
30 M
N
N
N
O
O
R
mGlu3 IC50
>
30 M
d
N
e
N
f
R3
N
N
O
N
HO
N
O
Kp = 0.30
R1
R1
R1
O
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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7
8
9
0
1
2
3
4
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7
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9
0
1
2
3
4
5
6
7
8
9
0
N
N
R2
R2
12
R2
N
O
NH2
NH2
N
O
11
13, R = OMe
4, R = NH2
N
g
1
F
aReagents and Conditions: (a) KOt-Bu, THF, dimethyl oxalate; then
HCl (aq), 42-85%; (b) 3-bromo-1H-pyrazol-5-amine, HCl (aq), EtOH, 78
C, 87-100%; (c) 10 mol% Pd(dppf), potassium vinyltrifluoroborate,
EtNi-Pr , n-PrOH:dioxanes (3:1), 90 °C, 51-93%; (d) OsO , NMO,
O11CH3
F
°
3
4
mGlu2 IC50 = 45 nM
mGlu3 IC50
30 M
Kp = 0.30
mGlu2 IC50 = 78 nM
mGlu3 IC50
30 M
Kp = 1.9
2
4
>
>
THF:DCM:H
2
O; then NaIO
, Dt-BAD, DCM, R
3
, MeOH, 150 ºC, µwave, 10-98%.
4
, 74-84%; (e) NaBH
4
, DCM:MeOH, 0 ºC,
3
OH, 0 ºC to 23 ºC, 15-79%; (g)
5
8-97%; (f) PPh
NH
3
Figure 1. Structures, pharmacology and rat CNS exposure data for
reported mGlu
NAM potency coupled with high rat CNS penetration.
2
NAMs 1-4. To date, only 4 displayed robust mGlu
2
allow significant diversity to sample replacements for the western N-
Me pyrazole moiety and -efficient entry to the more limited set of
of 4 precluded its use as in vivo tool compound (mouse CL
p
= 118
substituted aromatic moieties (Ar) that engender mGlu
2
NAM
mL/min/kg); however, 4 and related analogs are currently under
investigation as putative PET tracers to enable biomarker and
translational efforts.22-25 Here, we disclose further efforts towards the
development of mGlu
studies, and the discovery of two new series of mGlu
on either a functionalized pyrazolo[1,5-a]pyrimidine-5-carboxamide
core or a thieno[3,2-b]pyridine-5-carboxamide core from scaffold
hopping exercises.
potency/efficacy.22-25
We first explored the pyrazolo[1,5-a]pyrimidine-5-carboxamide
core 5, and developed a seven step synthetic route to access key
derivatives 14 (Scheme 1).26 Starting from commercially available
and appropriately substituted acetophenones 7, deprotonation and
trapping with dimethyl oxylate provided 8. Condensation of 8 with
3-bromo-1H-pyrazol-5-amine delivered the desired the 2-bromro
pyrazolo[1,5-a]pyrimidine core 9 in 87-100% yield. A subsequent
Suzuki cross-coupling installed the vinyl moiety affording 10, which
smoothly converted to the corresponding aldehyde 11 in good yield.
Sodium borohydride reduction gave primary alcohol 12, and a
substrate for diversification. Here, we first employed Mitsunobu
chemistry to install heteroaryl
2
NAM in vivo tool compounds for POC
NAMs based
2
RESULTS AND DISCUSSION
Our scaffold hopping strategy is depicted in Figure 2 and centered
on cyclization at the benzylic site to incorporate a fused 5-membered
heterocycle (with or without a heteroatom at the ring fusion site) to
produce two distinct 5,6-heterobicyclic systems, a pyrazolo[1,5-
a]pyrimidine-5-carboxamide core 5 or a thieno[3,2-b]pyridine-5-
carboxamide core 6. We desired a route that would
Table 1. Structures and rat mGlu
2
activities of analogs 14a
O
N
O
NH2
5
-membered fused
heterocycle
N
R3
N
NH2
O
N
R1
O
N
R
N
S
N
NH2
scaffold
hopping
Ar
N
N
N
5
R2
O
O
14
alternate
substituents
NH2
R
Entry R1
R2
R3
mGlu
nM)
(pIC ±SEM)
IC50
% Glu
Max±SEM
2
F
Ar
alternate
moieties
b
(
5
4
6
0
Figure 2. Scaffold hopping strategy from mGlu
novel pyrazolo[1,5-a]pyrimidine-5-carboxamide and thieno[3,2-
b]pyridine-5-carboxamide cores 5 and 6, respectively.
2
NAM 4 to arrive at
14a
H
F
N
>10000
<5)
-----
(
1
4b
F
OCH
F
3
288
.54±0.03
35.4±2.0
N
N
6
6
Scheme 1. Synthesis of pyrazolo[1,5-a]pyrimidine-5-carboxamide
analogs 14
a
14c
H
794
.10±0.07
2.4±0.4
CF3
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4d
F
F
102
.99±0.09
1.5±0.3
O
O
R3
N
N
N
6
NH2
1
2
3
4
5
6
7
8
9
NH2
CF3
CF3
N
R3
N
N
O
N
N
R4
1
4e
F
OCH
3
3
148
6.83±0.03
2.1±0.2
N
R1
R1
14f
H
F
224
19.7±10.8
N
R2
R2
6
.65±0.11
347
Br
1
5
16
mGlu2 IC50s 3.2 to 10 M
14g
F
OCH
F
4.2±7.4
mGlu2 IC50s >10 M
F3C
F3C
N
6.46±0.09
1
4h
H
Figure 3. Steep SAR. Analogs of 14 that encompassed either
functionalized aryl ethers 15 or secondary and tertiary amino-methyl
N
>10000
-----
(<5)
congeners 16 were either devoid of mGlu
significant activity relative to 14.
2
NAM activity, or lost
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
aCalcium mobilization assay with rmGlu
2
/TREx/G15-HEK cells
performed in the presence of an EC80 fixed concentration of glutamate,
values represent means from three (n = 3) independent experiments in
triplicate. bAmplitude of response in the presence of 30 µM test
compound as a percentage of maximal response to glutamate; average
of n = 3.
mGlu
2
NAMs before it were either poorly CNS penetrant (Kps
0.30) and/or displayed excessively high clearance in vitro and in
vivo, forcing their utility to be limited to putative PET tracers and not
<
in vivo POC tool compounds.23-25
and aryl ethers 13, followed by conversion of the methyl
ester to the final pyrazolo[1,5-a]pyrimidine carboxamide
analogs 14 in varying yields under microwave-assisted
conditions.
SAR for analogs 14 was steep (Table 1), with subtle variations
in substituents on the southern aryl ring (e.g., comparing 14a to 14b)
leading to >50-fold loss of mGlu
multiple potent mGlu NAMs resulted, with several (14b-g) below 1
M potency (with cLogP = 2.8-3.9), and 14d (mGlu IC50 = 102 nM,
pIC50 = 6.99±0.09, 1.5±0.3 % Glu min, cLogP = 3.92) was
comparable to 4. While these potent mGlu NAMs 14b-g showed
excellent CNS penetration (rat K s = 2.5 to 2.7 and Kp,uus = 0.4 to
.6), and are only the second mGlu NAM chemotype to display high
Needless to say, these data prompted a more in depth investigation
and optimization of the pyrazolo[1,5-a]pyrimidine-5-carboxamide
series; however, other heteroaryl ether congeners of 14 were largely
inactive or displayed poor in vitro and in vivo PK profiles. Utilizing
common intermediate 12, we also explored (Figure 3) aryl ether
congeners 15 (13 examples) and aminomethyl derivative 16 (10
examples), but all analogs 15 were inactive (IC50s >10 M), and
analogs 16 were weak to inactive (IC50s 3.2 to 10 M).
2
NAM functional potency. Still,
2

2
Thus, SAR proved quite steep, which led us to explore alternative
linkers from the pyrazolo[1,5-a]pyrimidine core to the western
pyridine heterocycle. Based on 1, we explored an aliphatic ethyl
linker terminating in functionalized pyridines to determine if a more
2
p
0
2
CNS penetration, their in vitro DMPK profiles were suboptimal.
While 14b-g did possess favorable fraction unbound in plasma (rat
‘
floppy’ presentation of the heterocycle would result in more robust
SAR with analogs 20. This synthesis proved straightforward
Scheme 2).26 Starting from bromo intermediate 9, a Sonogashira
and human f
homogenate (rat brain f
p,uus) and showed high predicted hepatic clearance in microsomes
rat CLhep >58 mL/min/kg, human CLhep >15 mL/min/kg).26 The one
exception, however, was 14c (mGlu IC50 = 794 nM, pIC50
.10±0.07, 2.4±0.4 % Glu min, cLogP = 3.77), which displayed
moderate fraction unbound in rat and human plasma (rat and human
s of 0.03 and 0.017, respectively) low unbound fraction in rat brain
= 0.007) and, for the first time within an mGlu NAM chemotype,
u
s 0.03 to 0.12), they were highly bound in brain
(
u
s 0.003 to 0.009, leading to lower pronounced
coupling with trimethylsilyl acetylene afforded 17, which was then
deprotected to provide the terminal acetylene 18 in 37% overall yield.
A second Sonogashira reaction with functionalized halopyridines
gave heterobiaryl acetylenes 19. Reduction of the alkyne and
conversion of the methyl ester to the primary carboxamide produced
the desired products 20.
K
(
2
=
6
f
u
(f
u
2
Scheme 2. Synthesis of pyrazolo[1,5-a]pyrimidine-5-carboxamide
analogs 20
a
moderate predicted hepatic clearance in microsomes (rat CLhep = 32.3
mL/min/kg, human CLhep = 6.6 mL/min/kg). To determine if there
was an in vitro:in vivo correlation (IVIVC), 14c was dosed in a
standard rat IV PK cassette (0.2 mg/kg per compound), where it
O
O
N
N
O
O
a
Si
b
9
N
N
N
N
R1
R1
p
demonstrated low plasma clearance in rat (CL = 10.0 mL/min/kg), a
long half-life (t1/2 = 4.28 hr) and a modest volume of distribution at
steady state (Vss = 3.31 L/kg). To confirm these exciting and
R2
R2
N
17
18
unprecedented PK data for an mGlu
discrete rat IV PK experiment (1 mg/kg) and found comparable,
favorable data (rat CL = 16.4 mL/min/kg, t1/2 = 5.53 hr, Vss = 6.59
L/kg). Moreover, 14c was highly selective for mGlu (>30 M versus
2
NAM, we then performed a
O
O
R3
N
R3
O
NH2
c
d,e
N
N
N
N
p
N
R1
N
R1
2
mGlu1,3-8). Despite the moderate functional potency, 14c was a
watershed moment for the field as all
R2
R2
19
20
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a
Reagents and Conditions: (a) TMS-acetylene, CuI, TEA, PdCl
2
(Ph
3
P)
2
,
intermediate gave 26 in good yields, followed by TBAF deprotection
o
o
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
48%, DMF, 120 C; (b) TBAF, THF, 0 C, 77%; (c) functionalized 3- or
4
Pd/C, MeOH, 72-80%; (d) NH
of the TIPS ether, which delivered linchpin 27. Alcohol 27 could be
bifurcated to deliver aryl and heteroaryl ethers 28, via a Mitsuobu
reaction followed by hydrolysis of the nitrile to the primary
carboxamide 29. Alternatively, 27 could be also converted into the
corresponding bromide with NBS, and then displaced with secondary
amines to afford aminomethyl congeners 30. Finally, hydrolysis of
o
-bromopyridine, CuI, Et
3
N, PdCl
2
(Ph
3
P)
2
, DMF, 150 C, 40%; (d) H
2
,
o
3
, MeOH, 150 C, µwave, 62-69%.
Like with analogs 15 and 16, SAR with congeners 20 was steep
Table 2) with few active analogs produced (5 total examples and the
(
majority had IC50s > 10 M). Of the actives, both an unsubstituted
3
2
the nitrile to the primary carboxamide 31, generated putative mGlu
2
2
-pyridyl 20a was a weak mGlu NAM (IC50 = 1,740 nM, cLogP =
NAMs.
.82), as was an unsubstituted 4-pyridyl analog 20b (IC50 = 1,050 nM,
The SAR for analogs 29 is shown in Table 3 for representative
examples. Once again, aryl ethers, such as 29a, regardless of
substitution patterns, were devoid of mGlu NAM activity. The N-
2
methyl pyrazole 29b, the thieno[3,2-b]pyridine-5-carboxamide
congener of 4, was ~20-fold less potent (IC50 = 1514 nM, cLogP =
cLogP = 2.35). This series produced a lone standout, 20c, the des-
oxy congener of 14c, which was ~9-fold more potent (mGlu
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
IC50 =
8
1
7 nM, pIC50 = 7.06±0.06, 2.3±0.2 % Glu min, cLogP = 3.85) than
4c, and comparable in potency to 4.25 In our standard rat
plasma:brain level (PBL) IV cassette (0.2 mg/kg per compound), 20c
showed good CNS penetration (K = 1.0, Kp,uu = 0.41), acceptable
fraction unbound in rat and human plasma (f s of 0.043 and 0.021,
respectively, and similarly low unbound fraction in rat brain, f
.006), but unacceptable predicted hepatic clearance in microsomes
rat CLhep = 66.7 mL/min/kg and human CLhep = 19.4 mL/min/kg).
3
4
.65), and the preferred heteroarylether moiety found in 14c, a 3-CF
-pyridine, also lost considerable activity (~20- fold) in the
3
-
p
u
thieno[3,2-b]pyridine-5-carboxamide series, example 29d (IC50
740 nM, cLogP = 5.24). Thus, it was clear that the SAR was quickly
shaping up to be divergent between the two 5,6-heterobicyclic series.
Several submicromolar mGlu NAMs did result from substituted 3-
pyridyl derivatives (29f-h and 29j-k), but potency barely exceeded
00 nM (cLogP = 4.45 to 5.26). Moreover, all of these analogs
showed high predicted hepatic clearance in microsomes (rat CLhep
60 mL/min/kg and human CLhep >17 mL/min/kg), but acceptable
CNS penetration (K s >2, Kp,uus <0.4, the latter moderate predicted
=
u
=
1
0
(
Attempts to mitigate the high clearance by deuteration of the ethyl
chain had no impact. Steep SAR in the pyrazolo[1,5-a]pyrimidine
forced us to move on to explore the thieno[3,2-b]pyridine-5-
carboxamide core 6 in hopes that more tractable SAR would result,
while maintaining the favorable CNS penetration and rat PK profile
of the pyrazolo[1,5-a]pyrimidine 14c.
2
7
>
p
hepatic clearance in microsomes (rat CLhep <45 mL/min/kg and
human CLhep <14 mL/min/kg), see Table 5.
Table 2. Structures and rat mGlu
2
activities of analogs 20a
O
R3
N
NH2
N
N
Scheme 3. Synthesis of thieno[3,2-b]pyridine analogs 29 and 31a
N
R1
N
O
N
N
N
a
b
c
R2
S
H
S
HO
S
TIPSO
S
20
Cl
Cl
Cl
Cl
21
22
23
24
Entry R1
R2
R3
mGlu
IC50 (nM)
% Glu
Max±SEM
2
b
N
N
(pIC50±SEM)
N
N
N
2
0a
0b
0c
H
F
F
1738
5.76±0.05
2.9±0.1
2.6±0.30
2.3±0.2
d
e,f
g
TIPSO
S
TIPSO
S
HO
S
N
R1
R1
R1
2
OCH
F
3
1047
.98±0.05
N
N
5
R2
R2
R2
2
H
87
25
26
27
7.06±0.06
O
N
CF3
N
N
NH2
aCalcium mobilization assay with rmGlu
/TREx/G15-HEK cells performed in the
i
2
R5
O
S
R5
S
O
presence of an EC80 fixed concentration of glutamate, values represent means from
R1
R1
b
three (n = 3) independent experiments in triplicate. Amplitude of response in the
presence of 30 µM test compound as a percentage of maximal response to
glutamate; average of n = 3.
h
R2
R2
27
28
29
O
Entry into the thieno[3,2-b]pyridine-5-carboxamide core was
accomplished via a nine-step synthetic route (Scheme 3), starting
with commercially available 7-chlorothieno[3,2-b]pyridine 21.26
Deprotonation at the 2-position with n-BuLi and quenching with
j
N
N
N
NH2
i
3
4
3R4RN
S
R RN
S
R1
R1
o
R2
R2
DMF (both at -78 C) afforded the desired aldehyde 22 in 64% yield.
Reduction to the alcohol 23 with NaBH , followed by silyaltion with
30
31
4
aReagents and Conditions: (a) n-BuLi, THF, -78 ºC, 20 min., then DMF,
78 ºC, 2 h, 64%; (b) NaBH , MeOH, 0 ºC to rt, 1h, 81%; (c) TIPS-Cl,
imidazole, DMF, 1h, 93%; (d) aryl boronic acid, Cs CO , Pd(dppf)Cl
O, 1,4-dioxanes, microwave, 125 ºC, 1h, 52-81%; (e) MCPBA, DCM,
h; (f) dimethyl carbamoyl chloride, TMS-CN, THF, 17 h, 50-74%; (g)
TIPS-Cl afforded the silyl ether 24. Next, standard Suzuki couplings
with appropriately functionalized aryl boronic acids provided 25 in
yields ranging from 52-81%. Installation of the cyano group in the
5-position via a two-step sequence through the pyridine N-oxide
-
4
2
3
2
,
H
1
2
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5
TBAF,
THF,
1h,
91-94%;
(h)
R OH,
PPh
3
, Dt-
very high clearance, not suitable for the development of in vivo POC
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
BAD, THF, 0 ºC to rt, 1 h, 28-93%; ; (i) KOTMS, THF, 70 ºC, 2 h, 8-
tool compounds.
3
4
6
3
0%; (j) NBS, PPh , DCM, 20 min., then HNR R , 1 h, 28-93%.
a
Table 4. Structures and rat mGlu
2
activities of analogs 31
O
Table 3. Structures and rat mGlu
2
activities of analogs 29a
N
NH2
O
N
3 4
R RN
S
NH2
R1
R3
O
S
R1
R2
31
R2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
29
Entry R1
R2
NR R
3
4
mGlu
nM)
% Glu
Max±SEM
2
IC50
b
(
Entry R1
R2
F
R3
mGlu
IC50
% Glu
Max±SEM
2
(pIC50±SEM)
b
(nM)
3
1a
1b
1c
H
H
F
F
OCH
OCH
F
N
O
3890
2.9±0.5
2.6±0.1
2.3±0.1
2.4±0.1
2.3±0.1
(
pIC50±SEM)
5
5
.41±0.09
2
9a
H
3
3
3
N
O
2512
.60±0.17
F
>10000
-----
(
<5)
N
1514
1.9±0.1
3
N
O
1413
5.85±0.05
2
9b
9c
H
H
F
F
N
5
.82±0.04
31d
31e
H
H
3631
5.44±0.06
2
N
S
F3C
N
>10000
-----
(<5)
F
550
6.26±0.01
N
2
9d
H
F
1740
2.3±0.2
O
N
5.76±0.30
1995
CF3
31f
31g
31h
31i
H
H
H
H
F
F
F
F
N
N
1738
5.76±0.20
2.2±0.2
4.1±0.4
29e
9f
9g
9h
29i
9j
9k
9l
29m
9n
9o
9p
H
H
H
H
H
H
H
H
H
H
F
F
F
16.8±2.3
29.3±11.7
2.2±0.1
13.2±3.6
7.2±3.2
3.2±0.3
3.3±0.3
26.23±2.7
6.9±0.8
2.6±0.4
2.7±0.1
2.8±0.1
5
.70±0.01
6607
H3CO
Cl
N
5
.18±0.04
2
871
6.06±0.05
N
>10000
N
(<5)
-----
2
F
676
6.17±0.01
N
1047
5.98±0.07
2.2±0.1
N
F
2
F
891
6.05±0.03
F
F
F
N
N
O
3
1j
H
F
1413
5.85±0.04
2.4±0.1
N
OCH
F
3
2570
.59±0.03
5
6
6
a
Calcium mobilization assay with rmGlu /TREx/G15-HEK cells performed in the
2
2
759
.12±0.03
presence of an EC80 fixed concentration of glutamate, values represent means from
three (n = 3) independent experiments in triplicate. Amplitude of response in the
presence of 30 µM test compound as a percentage of maximal response to
glutamate; average of n = 3.
b
N
2
F
741
.13±0.01
N
2
F
N
N
N
676
6.17±0.23
2
Table 5. In vitro DMPK and PBL data for select mGlu NAMs.
N
F
589
.23±0.06
316
Property
MW
cLogP
14c
20c
29g
393
4.76
77.1
29n
406
3.93
98.6
31e
6
N
N
431
3.67
92.6
429
3.85
83.4
411
4.36
77.1
2
OCH
OCH
OCD
3
3
3
6.50±0.13
TPSA
2
N
N
427
6.37±0.03
In vitro PK
parameters
Rat CLHEP
N
N
2
H
447
6.35±0.01
32.3
6.6
66.7
19.4
52.3
12.7
48.3
11.6
42.1
14.4
(mL/min/kg)
aCalcium mobilization assay with rmGlu
/TREx/G15-HEK cells performed in the
2
Human CLHEP
(mL/min/kg),
presence of an EC80 fixed concentration of glutamate, values represent means from
b
three (n = 3) independent experiments in triplicate. Amplitude of response in the
presence of 30 µM test compound as a percentage of maximal response to
glutamate; average of n = 3.
Rat f
Human f
Rat f brain
u
plasma
0.03
0.04
0.02
0.006
0.02
0.05
0.003
0.02
0.01
0.003
0.05
0.01
0.005
u
plasma 0.01
In vivo, 29n (IC50 = 316 nM, cLogP = 3.80) showed supra-hepatic
clearance in rat (CL = 389 mL/min/kg) with a very short half-life
1/2 = 14.3 min) and with a high volume (Vss = 6.49 L/kg), and thus
no IVIVC. Replacement of the OCH moiety with an OCD (29p),
in hopes to mitigate the high clearance, afforded no improvement.
Once again, efforts resulted in another mGlu NAM chemotype with
u
0.007
p
(t
Rat PBL
(IV, 0.2 mg/kg)
3
3
K
K
p
4.04
0.86
4.25
0.59
7.99
0.20
3.41
0.49
5.67
0.52
p,uu
2
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In one of the early series of mGlu
2
NAMs, represented by 2,23
Chemistry. All compounds were purified to >95% as determined by
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
analytical LCMS (214 nm, 254 nm and ELSD) as well as 1H and 13C
diverse amino methyl moieties were quite active; therefore, we
evaluated the related series of analogs 31 (Table 4). As with the
related pyrazolo[1,5-a]pyrimidine analogs 16, the majority of analogs
NMR and Hi-Res MS. The general chemistry, experimental
information, and syntheses of all other compounds are supplied in the
Supporting Information.
2
31 were inactive or weak mGlu NAMs (cLogP = 3.32 to 4.60), with
one exception, 31e (mGlu IC50 = 550 nM, pIC50 = 6.26±0.01, 2.3±0.1
% Glu min, cLogP = 4.36), which contains the same amine subunit
found in structurally unrelated NAM 2.23 As shown in Table 5, NAM
2
2
-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-7-(4-
fluorophenyl)thieno[3,2-b]pyridine-5-carboxamide (31e ). To a vial
containing 2-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-7-(4-
fluorophenyl)thieno[3,2-b]pyridine-5-carbonitrile (30e) (80.0 mg,
31e was also highly CNS penetrant (K
modest fraction unbound (rat and human f
respectively) and low unbound fraction in rat brain (f
p
= 5.62 and Kp,uu = 0.52) with
s of 0.055 and 0.015,
= 0.005).
u
0
.210 mmol, 1.0 equiv.) was added potassium trimethylsilanolate
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
u
(56.5 mg, 0.440 mmol, 2.1 equiv.) and THF (2.1 mL). The reaction
Importantly, 31e showed moderate predicted hepatic clearance in
microsomes (rat CLhep = 42.1 mL/min/kg and human CLhep = 14.4
o
mixture was heated to 70 C for 2 h at which time LCMS indicated
full consumption of the starting material. The reaction was cooled to
rt and then quenched with 0.200 mL 2 N HCl. The reaction mixture
was concentrated and then purified by reverse phase HPLC to give
3
mL/min/kg). Moreover, 31e was highly selective for mGlu (>30 M
2
versus mGlu1,3-8). Due to poor IVIVCs across both 5,6-heterobicyclic
systems, we immediately evaluated 31e in an in vivo rat IV PK study.
Here, 31e showed hepatic clearance (CL = 75 mL/min/kg) with a
p
reasonable half-life (t1/2 = 1.5 hr) driven by a high volume of
distribution at steady state (Vss = 7.42 mL/kg). In order to improve
exposure in vivo, we performed intraperitoneal (IP) dosing to avoid
first pass metabolism and, hopefully, achieve exposure at or above
1
2.6 mg of an off-white solid (39%). H NMR (400 MHz, CDCl
3
) δ
8
.03 (s, 1H), 7.83 – 7.76 (m, 1H), 7.68 – 7.59 (m, 2H), 7.14 – 7.01
(
(
m, 2H), 5.69 – 5.59 (m, 1H), 3.66 (d, J = 1.1 Hz, 2H), 3.60 – 3.47
m, 2H), 2.63 (dt, J = 10.4, 1.7 Hz, 2H), 1.70 (dd, J = 11.4, 9.9 Hz,
H), 0.97 (d, J = 6.3 Hz, 6H); 13C NMR (101 MHz, CDCl
64.80 (d, J(C,F) = 250.1 Hz), 162.31(d, J(C,F) = 250.1 Hz), 156.04,
50.60, 147.97, 144.04, 135.21, 133.74 (d, J(C,F) = 3.3 Hz), 133.71
2
1
1
3
) δ 167.36,
the mGlu
2
in vitro IC50 to enable POC studies. At 10 mg/kp ip, 31e
achieved total plasma concentrations of 1.07 M (Cmax) and 5.81 M
(d, J(C,F) = 3.3 Hz), 130.20 (d, J(C,F) = 8.4 Hz), 130.12 (d, J(C,F) =
(
(
AUC) with high total brain exposure (6.09 M (Cmax) and 32.9 M
AUC)), for a K of 5.67. When corrected for unbound brain
8.4 Hz), 123.36, 116.48 (d, J(C,F) = 21.9 Hz), 116.29, 116.26 (d,
J(C,F) = 21.9 Hz), 71.77, 59.49, 58.17, 19.19; HRMS (ESI):
calculated for C H FN O S [M]: 399.1417; found: 399.1419;
p
concentrations (based on rat brain homogenate binding data), brain
levels dropped to 30.4 nM (Cmax) and 165 nM (AUC). Thus, if in
vivo efficacy is driven by total brain levels, 31e is a suitable tool;
however, if driven by free brain levels, higher doses (>30 mg/kg) will
be required to achieve efficacious free brain levels (if 31e shows
2
1
22
3
2
+
LCMS R = 0.774, ES-MS [M+1] : 400.4.
T
ASSOCIATED CONTENT
dose-linear exposure).
physiological role and therapeutic potential of mGlu
However, to definitively dissect the
NAMs, a
Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
Experimental procedures and spectroscopic data for selected
compounds, detailed pharmacology and DMPK methods (PDF).
SMILES strings (CSV)
2
compound that can readily achieve free brain levels above the
functional IC50 at reasonable doses is required.
CONCLUSION
Corresponding Authors
In summary, we have reported on the discovery of two new 5,6-
*
Phone:
615-322-8700.
Fax:
615-343-3088.
E-mail:
heterobicyclic series of mGlu
a]pyrimidine-5-carboxamide core or
2
NAMs, based on either a pyrazolo[1,5-
thieno[3,2-b]pyridine-5-
craig.lindsley@vanderbilt.edu.
a
carboxamide core that provided advances in the field. First, both
series were highly CNS penetrant, with good functional potency and
selectivity versus the other seven mGlu receptor subtypes.
Funding Sources
This work was generously supported by the NIH and NIMH, GrantR01
MH 099269 (K.A.E.) and Grant R01 MH108498 (C.W.L). The authors
would also like to thank the Warren Family and Foundation for
establishing the William K. Warren, Jr. Chair in Medicine (C.W.L.).
2
Importantly, an analog within these series was the first mGlu NAM
to show attractive rat in vivo PK (low clearance and moderate half-
life). Interestingly, these new chemotypes did not always show an
IVIVC, making reliance on in vitro DMPK assays potentially
ABBREVIATIONS USED
2
problematic. While the ideal in vivo mGlu NAM did not result from
this scaffold-hopping and optimization campaign, advances in CNS
penetration coupled with rat PK were realized. Further optimization
efforts in other 5,6-heterobibcyclic systems are in progress and will
be reported in due course.
mGlu
concentration-response-curve; NAM, negative allosteric modulator;
, plasma/brain partitioning coefficient; Kp,uu, unbound brain
2
,
metabotropic glutamate receptor subtype 2; CRC,
K
p
partitioning coefficient; PBL, plasma:brain level; SAR, structure-
activity-relationships; POC, proof-of-concept
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ACS Paragon Plus Environment

Journal of Medicinal Chemistry
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improve potency and CNS penetration based on a truncated
picolinamide core. ACS Med. Chem. Lett. 2017, 8, 919-924.
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TABLE OF CONTENTS GRAPHIC
5
-membered fused
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