Discovery and SAR of novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5)

Article abstract of DOI:10.1016/j.bmcl.2015.01.038

We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu₅) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu₅ PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.

Full text of DOI:10.1016/j.bmcl.2015.01.038

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and SAR of novel series of imidazopyrimidinones and
dihydroimidazopyrimidinones as positive allosteric modulators of
the metabotropic glutamate receptor 5 (mGlu5)
a
a
María Luz Martín-Martín a, , José Manuel Bartolomé-Nebreda , Susana Conde-Ceide ,
⇑
Sergio A. Alonso de Diego a, Silvia López a, Carlos M. Martínez-Viturro a, Han Min Tong a, Hilde Lavreysen b,
Gregor J. Macdonald b, Thomas Steckler b, Claire Mackie c, Thomas M. Bridges d,e,f, J. Scott Daniels d,e,f
,
Colleen M. Niswender d,e,f, Meredith J. Noetzel d,e,f, Carrie K. Jones d,e,f, P. Jeffrey Conn d,e,f
Craig W. Lindsley d,e,f,g, Shaun R. Stauffer d,e,f,g
,
a Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain
b Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium
c Discovery Sciences ADME/Tox, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium
d Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
e Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
f Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA
g 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:
We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyri-
midinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Explo-
ration of several structural features in the western and eastern part of the imidazopyrimidinone core
and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and effi-
cacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an
amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in pre-
clinical species precluded any further in vivo evaluation.
Received 9 December 2014
Revised 16 January 2015
Accepted 19 January 2015
Available online xxxx
Keywords:
Positive allosteric modulator (PAM)
Metabotropic glutamate receptor 5 (mGlu5)
Imidazopyrimidinone
Ó 2015 Elsevier Ltd. All rights reserved.
Dihydroimidazopyrimidinone
Schizophrenia
Schizophrenia is a devastating psychiatric illness that afflicts
approximately 1% of the world population. Current therapies, based
on the direct modulation of the monoaminergic system (dopamine
and serotonin), are associated with severe adverse effects and do
not provide sufficient relief across all symptom domains of the dis-
ease.1,2 Therefore, new treatments, possibly acting via different
neurotransmitter systems are under investigation. Among the dif-
ferent existing alternatives, the modulation of the glutamatergic
system has emerged as an obvious candidate.3,4 Glutamate
glutamate receptors (mGlu1 to mGlu8).5 Among the different
mGlus, the mGlu5 receptor is structurally and pharmacologically
associated with the NMDA receptor playing prominent roles in syn-
aptic plasticity, cognition, learning and memory process1,6 and it
has been reported that the activation of mGlu5 potentiates NMDA
receptor function.7 Provided the advantages associated to PAMs
over orthosteric agonists, that is, increased subtype selectivity,
improved chemical tractability, better modulatory control of recep-
tor function and low propensity for receptor desensitization; the
potentiation of mGlu5 via activation at allosteric sites could be a
preferred pharmacological mechanism to indirectly correct the
hypothesized NMDA receptor hypofunction in schizophrenia.2,8
Consequently, the development of PAMs of mGlu5 has emerged as
a potentially viable way to treat positive symptoms9,10 and also
improve cognitive deficits11,12 in schizophrenia.
(L
-glutamic acid) is the major excitatory neurotransmitter in the
mammalian central nervous system (CNS), where it mediates its
effects through three ionotropic receptors -amino-3-
hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-
(D,L-a
D
-aspartate (NMDA) and kainate) and eight metabotropic
After nearly a decade of mGlu5 PAMs research, a variety of
⇑
Corresponding author. Tel.: +34 925 245792; fax: +34 925 245771.
E-mail address: mlmartin@its.jnj.com (M.L. Martín-Martín).
structurally different chemotypes have been reported.13 Among
http://dx.doi.org/10.1016/j.bmcl.2015.01.038
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Martín-Martín, M. L.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.01.038

2
M. L. Martín-Martín et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
them, we have recently described the discovery of phenoxy-con-
taining mGlu5 PAMs derived from dihydrothiazolopyridone14 and
naphthyridinone15 bicyclic cores. As a progression of this work,
and in order to further optimize the in vitro and in vivo potencies
of dihydrothiazolopyridone 1, we envisioned the replacement of
the thiazolyl ring system by other aromatic five-membered rings
(Fig. 1).
yielding intermediate 7. De-chlorination was performed under
hydrogenation conditions affording analogue 3a. This key com-
pound was then derivatized to the desired N-aryl imidazopyrimid-
inones 3e and 3h–3n, by reaction either with p-fluoroiodobenzene
(3e) or various heteroaryl halides (3h–3n) using a copper iodide–
diamine ligand protocol to perform a modified Ullman-type lactam
cross-coupling.
Our initial approach involved the direct replacement by an
oxazolyl ring affording dihydrooxazolopyridones 2. Encouraged
by a comparable in vitro mGlu5 PAM activity to dihydrothiazolo-
pyridone 1 series, the most potent analogues were tested in the
reversal of amphetamine-induced hyperlocomotion (AIH) in rats,
a predictive model of antipsychotic activity.10a,16 Unfortunately,
none of the analogues tested showed robust in vivo activity after
oral dosing. This lack of relevant in vivo activity could be explained
by the limited absorption observed for these derivatives and thus,
our subsequent exploration focused on the identification of other
chemotypes with different properties (i.e., electronics, basicity,
lipophilicity, etc.) that could eventually lead to an improvement
in the in vivo efficacy. In this Letter we report our efforts towards
the synthesis and optimization of imidazopyrimidinones 3 and
dihydroimidazopyrimidinones 4 as novel series of mGlu5 PAMs.
Synthesis of these 5,6-bicyclic systems was achieved following
two parallel approaches that allowed the introduction of diverse
substituents in the eastern and western part of the targeted mole-
cules, as shown in Schemes 1 and 2. Our first strategy was focused
on the preparation of the key compound 3a, with the aim to survey
the eastern diversity in the last step (Scheme 1). Condensation of
chloropyrimidine 5 with 1,3-dichloroacetone under acidic condi-
tions, following a procedure already reported in the literature
afforded intermediate 6.17 Introduction of phenoxy group in the
western part of the molecule using potassium carbonate as base
was followed by the selective hydrolysis of the thiomethyl group
Unfortunately, functionalization in the eastern amide moiety
with alkyl substituents or other aryl halides following the same
Ullman-type conditions was unsuccessful and for this purpose,
the approach outlined in Scheme 2 was used. This second strategy
allowed the introduction of several alkyl and aryl moieties and also
to survey the substitution in the western part of the molecule.
Furthermore, this approach could be additionally applied to the
introduction of small groups in the 7 and 8-positions of the imi-
dazopyrimidinone core (Scheme 2). Thus, for the functionalization
with alkyl and aryl groups in the eastern part of the molecule we
started from commercially available cytosine derivatives 9. The
reaction of 9 with a variety of alkyl halides using tetrabutylammo-
nium hydroxide as base allowed the selective alkylation on the lac-
tam. On the other hand, for the functionalization with aryl moieties
a Chan-Lam-type copper-catalyzed coupling reaction between
cytosine derivatives 9 and the corresponding aryl boronic acids
as depicted in Scheme 2 was followed.18 Then, condensation with
1,3-dichloroacetone followed by introduction of the corresponding
phenoxy or pyridyloxy group in the western part of the molecule,
via reaction with the corresponding phenols or hydroxypyridines
using potassium carbonate as base, allowed the preparation of ana-
logues 3b–3g, 3o–3s and 3u. The 8-methyl analogue 3v was pre-
pared by Suzuki-type coupling reaction between methylboronic
acid and intermediate 13, synthesized following a similar synthetic
route as described before but starting from the corresponding
substituted iodocytosine 12 as shown in Scheme 2.
Alternate Alkyl,
Aryl, Heteroaryl
Alternate Aryl,
Heteroaryl
Small groups in
central core
O
O
S
N
X
Y
N
N
Ph
O
N
O
Single or double
bond
1
EC50 = 1195 nM
Other 5-membered
Heterocycles
O
O
O
R1
R1
R1
O
N
N
N
N
N
N
R2
R2
N
R2
O
N
O
O
4
2
3
Figure 1. Evolution strategy of dihydrothiazolopyridone 1 to other 5,6-bicyclic systems.
SMe
SMe
N
O
O
O
R1
a
b, c
d
e
Cl
PhO
PhO
PhO
N
N
N
N
NH
Cl
N
NH
N
N
N
N
N
N
H2N
Cl
Cl
5
6
7
3a
3e, 3h-3n
Scheme 1. Reagents and conditions: (a) 1,3-dichloroacetone, AcOH, 110 °C, 16 h, 44%; (b) PhOH, K2CO3, ACN, 50 °C, 18 h, 53%; (c) LiOH, H2O/THF, 50 °C, 4 h, 98%; (d) Pd(OH)2/
C, H2 atm, Et3N, AcOEt/MeOH, 50 °C, 45 psi, 16 h, in a Parr reactor, 92%; (e) R1X, CuI, N,N0-dimethylethylenediamine, K2CO3, toluene, 120 °C, 16 h, 22–73%.
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M. L. Martín-Martín et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
O
O
O
O
R1
R
R1
R
R1
R
a
b
c
Cl
R2O
NH
N
N
N
N
N
N
N
7
N
N
R
H2N
H2N
3b - 3g, R=H, R2=Ph
3o - 3s, R=H, R2=2-Py
3u, R= Me, R2=Ph
9, R=H, Me
10, R=H, Me
11, R=H, Me
d
O
O
N
O
R1
R1
R1
b, c
R2O
R2O
e
N
N
N
N
N
N
N
H2N
12, R1=p-F Ph
8
I
I
3v, R1=p-F Ph
13, R1=p-F Ph
R2=Ph
R2=Ph
Scheme 2. Reagents and conditions: (a) for R1 = Alkyl: R1X, BuN4OH, DMF, rt, 2 h, 57–77% and for R1 = Aryl or heteroaryl: R1B(OH)2, Cu(OAc)2, TMEDA, MeOH/H2O, rt, 16 h,
48–65%; (b) 1,3-dichloroacetone, DMF, 150 °C, 30 min, microwave irradiation, 15–75%; (c) R2OH, K2CO3, ACN, 90 °C, 18 h, 58–95%; (d) I2, NaIO4, H2SO4, AcOH/water, 80 °C, 4 h,
84%; (e) MeB(OH)2, Pd(PPh3)4, K2CO3, 1,4-dioxane/DMF, 150 °C, 45 min, microwave irradiation, 72%.
O
O
O
O
Br
R1
R1
R1
R2O
R1
R2O
R2O
a
b
R2O
c
N
N
N
N
N
N
N
N
N
N
N
N
3
4
14, R1=p-F Ph
4l, R1=p-F Ph
R2=Ph
R2=Ph
d
d
O
O
Cl
Cl
R1
R1
R2O
R2O
N
N
N
N
N
N
3t, R1=p-F Ph
4k, R1=p-F Ph
R2=Ph
R2=Ph
Scheme 3. Reagents and conditions: (a) Pd(OH)2/C, H2 atm, MeOH, 50 °C, 50 psi, 16 h, in a Parr reactor or Raney-Ni, 80 °C, full hydrogen mode, DMF/MeOH in an H-Cube
reactor, 5–78%; (b) NBS, benzoyl peroxide, DCE, rt, 16 h, 35%; (c) MeB(OH)2, Pd(PPh3)4, K2CO3, 1,4-dioxane/DMF, 150 °C, 45 min, microwave irradiation, 56%; (d) NCS, DMF,
150 °C, 15–20 min, microwave irradiation, 27–55%.
Hydrogenation of the double bond in analogues 3 was per-
formed using palladium hydroxide on carbon or Raney nickel as
catalysts at high temperatures (Scheme 3). All attempts to reduce
the double bond in compounds with substitution in the 7 or 8-
positions different than hydrogen were unsuccessful. Finally, func-
tionalization in the imidazole ring was achieved by halogenation of
the corresponding derivatives 3 and 4 with N-chlorosuccinimide
(NCS) or N-bromosuccinimide (NBS). Subsequent Suzuki-type cou-
pling reaction of 14 with methylboronic acid yielded analogue 4l as
depicted in Scheme 3.
not improve the in vitro potency (EC50 >10 lM), which was still
significantly decreased compared with analogue 1. According to
previous work,14 the functionalization with an alkyl chain of
increased size such as cyclopropylmethyl (3c) interestingly
induced a significant improvement in the in vitro mGlu5 PAM
activity, resulting in a potency in the same range as that of the
dihydrothiazolopyridone prototype 1, although with reduced effi-
cacy. Comparable potency again but significantly improved effi-
cacy (93% Glu Max) was achieved by the introduction of a
bulkier aromatic benzyl group in 3d.
The compounds synthesized were profiled in a human mGlu5
low receptor expression cell line using a ‘triple add’ calcium mobi-
lization assay, allowing the detection of agonism as well as positive
and negative allosteric modulation simultaneously.19 The most rel-
evant SAR trends for the imidazopyrimidinones 3 are shown in
Table 1. Initial exploration was focused on the introduction of sub-
stituents in the amide moiety with the aim to further improve the
marginal activity observed for the unsubstituted analogue 3a
We next evaluated the effects of the introduction of different
substituted aryl and heteroaryl rings on the lactam. Based on our
previous results,14 SAR investigation started with the introduction
of fluorine-containing phenyl rings (3e–3g) resulting in a remark-
able improvement in the mGlu5 PAM activity. Among this small
set, the para- and the 3,4-substitutions (3e and 3g) proved to be
more beneficial than the meta- (3f) in terms of potency and effi-
cacy. Additionally, the meta-substitution was also found detrimen-
tal for the metabolic stability in rat liver microsomes (RLM). In a
second step, we studied the effects of the replacement of the phe-
nyl ring by more polar and weakly basic pyridines prioritizing
the 2-substituted pyridine analogues over the 3 or 4 regioisomers
(EC50 >30 lM, 19% Glu Max). Following a similar strategy to the
dihydrothiazolopyridone series (1),14 we first targeted the intro-
duction of alkyl substituents. Thus, N-methylation in compound
3b, despite having a positive effect in efficacy (67% Glu Max) did
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4
M. L. Martín-Martín et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Table 1
Structures and activities of substituted imidazopyrimidinones 3
R3
3
O
R1
N
N
R
R2
O
7
N
1
a
Compd
R1
H
R2
R3
R
mGlu5 pEC50
( SEM)
mGlu5 EC50
(nM)
% Glu maxb
( SEM)
HLMc
(%)
RLMc
(%)
3a
3b
3c
3d
H
H
H
H
H
H
H
H
<4.52d
>30,000
<10,000
1120
19
n.t.e
n.t.e
n.t.e
n.t.e
n.t.e
n.t.e
n.t.e
n.t.e
<5d
67 4.2
47 3.7
93 5.0
5.95 0.03
5.80 0.06
1590
F
3e
3f
H
H
H
H
H
H
6.51 0.15
6.29 0.02
6.64 0.05
310
514
230
83 9.1
69 0.9
93 11.7
14
27
47
71
F
F
3g
n.t.e
n.t.e
F
F
3h
H
H
6.23 0.05
587
87 10.2
n.t.e
n.t.e
N
N
Me
Me
3i
3j
H
H
H
H
5.69 0.14
5.45 0.11
2000
3580
84 15.4
64 10.3
n.t.e
n.t.e
n.t.e
n.t.e
N
Me
3k
H
H
5.29 0.07
5100
64 9.0
n.t.e
n.t.e
N
N
3l
H
H
H
H
6.55 0.08
6.43 0.05
284
375
87 13.6
77 8.0
66
8
90
50
N
F
3m
Me
F
N
Me
3n
H
H
6.36 0.07
435
77 11.9
17
49
N
F
F
F
3o
3p
H
H
H
H
6.64 0.05
6.43 0.06
230
375
91 11.1
85 11.6
30 2.8
88 12.4
65 5.5
13
11
28
29
F
F
F
F
F
Me
3q
3r
3s
3t
H
H
H
Cl
H
H
H
H
6.46 0.11
5.50 0.09
<5d
344
n.t.e
n.t.e
n.t.e
6
n.t.e
n.t.e
n.t.e
73
N
3170
<10,000
218f
N
6.66 0.08f
5
0.0.5f
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5
Table 1 (continued)
a
Compd
R1
R2
R3
R
mGlu5 pEC50
( SEM)
mGlu5 EC50
(nM)
% Glu maxb
( SEM)
HLMc
(%)
RLMc
(%)
F
F
3u
3v
H
H
7-Me
8-Me
5.68 0.08
6.00 0.06f
2070
60 4.5
16 3.8f
n.t.e
36
n.t.e
71
1000f
a
b
c
Calcium mobilization assay using HEK293 cells stably expressing rat mGlu5 receptors; values are the average of three or more independent determinations.
Expressed as amplitude of response using 30 M test compound (percentage of maximal response vs 100 M glutamate).
HLM and RLM data refer to % of compound metabolized after incubation of tested compound with human and rat microsomes, respectively, for 15 min at 1
l
l
l
M
concentration.
d
Data obtained from a single experiment not replicated.
Not tested.
Antagonists/NAMs, data represents pIC50/IC50 from EC80 window and % Glu represents Emin not Emax
e
f
.
(3h–3n).14 Thus, while only a slight decreased PAM activity was
shown with compound 3h, the corresponding 2-pyridyl analogue
of 3e; the introduction of a methyl substituent in 3-, 4- and 5-posi-
tion of the 2-substituted pyridine ring (analogues 3i–3k), revealed
a substantial loss of potency and efficacy. The recovery of both
properties was achieved with a more basic analogue (3l) although
unfortunately, this was accompanied by a high metabolic turnover
in human liver microsomes (HLM) and RLM. Similarly, despite the
combination of fluorine and methyl in the disubstituted pyridyl
congeners 3m and 3n resulted in good in vitro PAM activity and
efficacy, the improvement in metabolic stability in RLM was only
moderate.
Encouraged by the promising profile of 3e, we next decided to
evaluate the influence of the western aromatic ring in our mole-
cules keeping constant for that purpose the para-fluorophenyl sub-
stitution on the amide moiety. Thus, the introduction of a fluorine
atom in meta- and para-positions of the phenoxy ring resulted in
similar PAM potencies and efficacies (EC50 = 230 nM, 91% Glu
Max for 3o and EC50 = 375 nM, 85% Glu Max for 3p) to the parent
analogue 3e. Similarly, the introduction of a methyl group also
retained the in vitro activity although a remarkable decrease in
efficacy was observed (3q, 30% Glu Max). In contrast, replacement
of the western phenyl by a pyridine was found to be clearly detri-
mental for mGlu5 activity (compounds 3r and 3s).
Additionally, we also investigated the influence of small groups
in different positions of the imidazopyrimidinone core, keeping
again the para-fluorophenyl substitution on the lactam (com-
pounds 3t–3v). This brief SAR survey led to an unexpected ‘molec-
ular switch’ that changed the mode of the pharmacology. Thus, the
introduction of a chlorine atom in the 3-position (3t) or a methyl
substituent in the 8-position (3v) provided weak to moderate
mGlu5 antagonists or negative allosteric modulators (NAMs) with
IC50s of 218 and 1000 nM, respectively, and with additionally
reduced metabolic stability in RLM. On the contrary, the 7-methyl
analogue 3u still behaved as mGlu5 PAM although with a greatly
reduced potency (EC50 = 2070 nM, 60% Glu Max) compared to par-
ent congener 3e.
In parallel to our exploration of the imidazopyrimidinone series
3, we also synthesized a number of the more flexible dihydroimi-
dazopyrimidinones 4 by hydrogenation of a set of analogues 3 pre-
senting identified preferred modifications. SAR of this series is
summarized in Table 2. Alkyl analogues in the lactam were found
unstable under basic conditions20 and thus only aryl and hetero-
aryl substitutions were explored. Interestingly, this small library
proved more productive than the previous one, providing several
analogues with mGlu5 PAM activities below 250 nM. The specific
comparison among pairs of analogues presenting fluorine decora-
tions in the eastern aromatic aryl confirmed this trend; with a
noticeable ꢀ3.5 fold increase in potency for the para-fluorophenyl
derivative 4a versus 3e and less prominent 1.8–2.4 increase for the
meta- and the 3,4-difluoro substituted analogues (4b and 4c vs 3f
and 3g, respectively). The same beneficial effect was also observed
for the pyridyl-containing pairs (4d–4f vs 3h,i,m) with mGlu5
potency increases ranging from 1.6 to 4.1 fold, however counter-
parts 4g and 3n showed comparable activity. On the other hand,
the increased flexibility in the central core did not result in any
outstanding effect on microsomal stability.
Analogously, the introduction of a fluorine atom in the meta-
(4h) and para-position (4i) of the western aryl, greatly increased
mGlu5 potency up to ꢀ3.3 fold versus series 3 corresponding coun-
terparts, maintaining also a high efficacy. Gratifyingly, this explo-
ration yielded analogue 4h, the most potent mGlu5 PAM across
the two series described herein (EC50 = 69 nM, 72% Glu Max). How-
ever, the introduction of a methyl group in the meta-position (4j)
contributed to a significant loss in efficacy in comparison with
the other dihydroimidazopyrimidinones 4, confirming the ten-
dency previously observed for series 3 (47% Glu Max for 4j vs
30% Glu Max for 3q).
Similarly to chemotype 3, the introduction of substituents in
the 3-position of the dihydroimidazopyrimidinone core was
responsible again for a change in the mode of pharmacology and
resulted in compounds that behaved as antagonists/NAMs. Thus,
the introduction of a chlorine atom in 4k or a methyl group in 4l,
afforded mGlu5 antagonists/NAMs of moderate potency (133 and
529 nM, respectively). These data demonstrated again that with
very subtle structural changes, a reasonably potent PAM can be
transformed into an antagonist/NAM of comparable potency, con-
firming the findings previously reported for other chemotypes.15,21
After this initial exploration, analogues 3e and 4a were selected
as representative examples from both chemotypes for additional
characterization (Table 3). Thus, besides increased flexibility, 4a
shows also a slightly reduced cLogP (0.5 log units). Both analogues
were found adequately stable in HLM and RLM with no significant
differences in the extent of metabolism. Additionally, in a cocktail
assay using HLM and known substrates, 4a did not show any rele-
vant inhibition of the major human cytochrome P450 (CYP)
enzymes (2C9, 2D6, 3A4, 1A2) (IC50s >20
to display moderate CYP inhibitory activity on 1A2 (IC50 = 9.3
others IC50 >20 M). Finally, 4a showed a slightly higher unbound
fraction in both human and rat plasma compared with 3e.
lM), while 3e was found
lM,
l
Subsequent selectivity profiling against the other mGlu recep-
tors (mGlu1–4,6–8) revealed that both compounds were also active
as full mGlu3 NAMs, (IC50 = 630 nM for 3e and 290 nM for 4a),
resulting in moderate functional selectivities for mGlu5 of ꢀ2 fold
for 3e and ꢀ3 fold for 4a respectively (other mGlu EC50 >10
lM).
An analogous dual profile had already been observed for similarly
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6
M. L. Martín-Martín et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Table 2
Structures and activities of substituted dihydroimidazopyrimidinones 4
R3
3
O
R1
N
N
R2
O
7
N
1
R1
R2
R3
mGlu5 pEC50
( SEM)
mGlu5 EC50
(nM)
% Glu maxb
( SEM)
HLMc
(%)
RLMc
(%)
a
Compd
F
4a
4b
4c
H
H
H
7.07 0.02
6.66 0.03
6.88 0.06
86
70 0.7
82 9.2
91 12.6
18
20
10
19
78
37
218
130
F
F
F
F
4d
4e
4f
H
H
H
6.44 0.08
6.31 0.02
6.74 0.02
359
485
183
66 2.1
74 9.6
91 13.0
1
14
98
93
N
N
Me
35
31
F
Me
F
N
Me
4g
H
6.43 0.08
371
87 16.1
n.t.d
n.t.d
N
F
F
F
4h
4i
H
7.16 0.01
6.70 0.04
6.55 0.07
6.88 0.05e
6.28 0.09e
69
72 0.7
88 12.2
47 3.3
14 4.8e
0
29
H
197
285
133e
529e
3
11
F
F
F
Me
4j
H
n.t.d
n.t.d
21
n.t.d
n.t.d
46
4k
4l
Cl
Me
F
6
1.4e
a
b
c
Calcium mobilization assay using HEK293 cells stably expressing rat mGlu5 receptors; values are the average of three or more independent determinations.
Expressed as amplitude of response using 30 M test compound (percentage of maximal response vs 100 M glutamate).
HLM and RLM data refer to % of compound metabolized after incubation of tested compound with human and rat microsomes respectively, for 15 min at 1
l
l
l
M
concentration.
d
Not tested.
e
Antagonists/NAMs, data represents pIC50/IC50 from EC80 window and % Glu represents Emin not Emax
.
Table 3
Comparative profile of compounds 3e and 4a
% Glu maxb
( SEM)
clogPc
mGlu3 EC50
(nM)
HLMd
(%)
RLMd
(%)
hPPBe
(%)
rPPBe
(%)
a
Compd
mGlu5 EC50
(nM)
3e
4a
310
86
83 9.1
70 0.7
3.95
3.42
630
290
14
18
27
19
96.4
90.3
93.1
88.1
a
b
c
For the mGlu5 PAM assay see Tables 1 and 2.
Expressed as amplitude of response using 30
Calculated with Biobyte software.
l
M test compound (percentage of maximal response vs 100 lM glutamate).
d
HLM and RLM data refer to % of compound metabolized after incubation of tested compound with human and rat microsomes respectively, for 15 min at 1 lM
concentration.
e
Plasma protein binding, human and rat.
substituted N-aryl analogues within our naphthyridinone series.15
Although the biological relevance of the mGlu3 receptor is still not
well understood, inhibition of mGlu3 has been hypothesized to
have potential therapeutic utility in the treatment of neurological
and psychiatric disorders.22 Based on its mGlu5 PAM potency and
efficacy, higher selectivity versus mGlu3, reduced cLogP, superior
Please cite this article in press as: Martín-Martín, M. L.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.01.038

M. L. Martín-Martín et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
7
In summary, further optimization of our initial dihydrothiazol-
opyridone lead 1 resulted in two novel series of imidazopyrimid-
inones and dihydroimidazopyrimidinones as mGlu5 PAMs.
Parallel SAR investigation of both series and further DMPK profil-
ing of representative prototypes revealed dihydroimidazopyri-
midinone 4a as a highly potent and efficacious mGlu5 PAM
(EC50 = 86 nM, 70% Glu Max) and moderately potent mGlu3
NAM (IC50 = 290 nM, 3% Glu Max). 4a possessed an adequate PK
profile in rats and showed robust dose-dependent effects in a pre-
clinical model predictive of antipsychotic efficacy. However, the
presence of CNS-mediated adverse effects in preclinical species
precluded any further in vivo evaluation. Keeping in mind that
more studies are necessary to address ongoing questions concern-
ing the therapeutic index of mGlu5, further efforts within these
and related series are in progress and will be reported in due
course.
Acknowledgments
Figure 2. Dose-dependent effect and calculated terminal unbound brain of 4a on
the reversal of amphetamine-induced hyperlocomotion in rats.
Vanderbilt Center for Neuroscience Drug Discovery (VCNDD)
research was supported by grants from Janssen Pharmaceutical
Companies of Johnson
(NS031373 and MH062646).
& Johnson and in part by the NIH
CYP profile and higher unbound fraction in plasma, 4a was selected
for further in vivo pharmacokinetic (PK) and pharmacological
evaluation.
References and notes
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moderate clearance (CLp = 23.3 mL/min/kg) and a terminal half-life
(t1/2) of 0.93 h. Evaluation of drug concentrations in portal vein,
plasma and brain (0.5, 1.0, 2.0, 4.0 and 7.0 h) revealed a moderate
first-pass effect (Ehep = 0.43) with relatively low volume of
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l
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24
in vitro mGlu5 PAM EC50
.
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