Discovery of novel N-1 substituted pyrazolopyrimidinones as potent, selective PDE2 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2021.128082

A focused SAR study was conducted on a series of N1-substituted pyrazolopyrimidinone PDE2 inhibitors to reveal compounds with excellent potency and selectivity. The series was derived from previously identified internal leads and designed to enhance steric interactions with key amino acids in the PDE2 binding pocket. Compound 26 was identified as a lead compound with excellent PDE2 selectivity and good physicochemical properties.

Full text of DOI:10.1016/j.bmcl.2021.128082

Bioorg. Med. Chem. Lett. 44 (2021) 128082
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of novel N-1 substituted pyrazolopyrimidinones as potent,
selective PDE2 inhibitors
a
,
*
a
a
a
a
Gregori J. Morriello , Michael P. Dwyer , Yili Chen , Anthony T. Ginetti , Shimin Xu ,
d
d
d
d
b
Jun Lu , Pravien Abeywickrema , Deping Wang , Alejandro Crespo , Tamara D. Cabalu ,
d
d
d
c
Jonathan E. Wilson , Shawn J. Stachel , Daniel V. Paone , Christopher Sinz
a
Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
b
Drug Metabolism, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA
c
Discovery Chemistry, Merck & Co., Inc., 213 E. Grand Avenue, South San Fransisco, CA 94080, USA
d
Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA
A R T I C L E I N F O
A B S T R A C T
Keywords:
PDE2
A focused SAR study was conducted on a series of N1-substituted pyrazolopyrimidinone PDE2 inhibitors to reveal
compounds with excellent potency and selectivity. The series was derived from previously identified internal
leads and designed to enhance steric interactions with key amino acids in the PDE2 binding pocket. Compound
cAMP
cGMP
2
6 was identified as a lead compound with excellent PDE2 selectivity and good physicochemical properties.
Pyrazolopyrimidinone
Phosphodiesterases (PDE) play a key role in the degradation of sec-
some selectivity over the other PDE members. Herein, we describe a new
series of PDE2 inhibitors to which we based the core of the compound on
“flipping” the pyrazolopyrimidinone core discovered previously. We
describe how we developed chemistry to make the new analogs and how
we proceeded to identify a new lead class of compounds for PDE2
inhibition.
′
′
ondary messengers 3 ,5 - cyclic adenosine monophosphate (cAMP) and
′
′
1
3
,5 -cyclic guanosine monophosphate (cGMP). There are 11 PDE
families which have different tissue distribution and possess different
selectivity for cAMP and cGMP.2 Both cAMP and cGMP have been
implicated in playing a key role in intracellular signaling, neuronal
plasticity, and long-term potentiation which could improve cognitive
While our early work in the PDE2 area focused upon pyrazolopyr-
function and memory.3
–5
imidinone core derivatives of type A, one could envisage the idea of a
16
PDE2 is a dual-substrate enzyme which is stimulated by cGMP and
simple flip of the pyrazolo ring would lead to compounds of type B. This
may engender divergent off-target and pharmacokinetic profiles while
maintaining the similar display of critical pharmacophores. The SAR for
this series could easily be probed using a combination of N-alkylation
6
which degrades both cAMP and cGMP. PDE2 is highly expressed in the
human brain where it is localized in the cortex, hippocampus, and
7
striatum. PDE2 inhibition elevates the levels of these cyclic nucleotides
which could enhance cognitive and hippocampal function, which are
chemistry (R
2
) coupled with a Suzuki coupling strategy to install the
1
altered in diseases such as schizophrenia and Alzheimer’s disease. To-
requisite -branching benzylic moiety. This chemistry is well suited for
α
wards this end, there has been a considerable effort to identify selective,
brain penetrant PDE2 inhibitors towards the treatment of cognitive
disorders.8 Fig. 1 summarizes some of these compounds; from early
compounds, like Bay 60–7550 and TAK-915, to more recent derivatives
from Janssen and Pfizer and several reviews have recently covered this
both library and singleton syntheses to push the SAR far more rapidly
than the pyrazolopyrimidinones of type A.
Initial chemistry efforts focused upon preparation of the N1-H and
N1-methyl substituted core compounds shown in Scheme 1. Treatment
of either 1 or 2 with benzyl ethanimidiothioate hydrochloride under
basic conditions afforded bicyclic cores 3 or 4 respectively that upon
treatment with NBS afforded compounds 5 and 6. Suzuki coupling with
9
–14
area.
We had recently disclosed an inhibitor series that was identified via
fragment based and high throughput screening.15 These pyrazolopyr-
imidinones proved to have good binding affinity to PDE2 and displayed
the requisite vinyl boronate in the presence of Pd(OAc)
2
and sodium
′
′′
3,3 ,3 - phosphinetriyltribenzenesulfonate hydrate afforded olefins 7
*
Corresponding author.
E-mail address: greg_morriello@merck.com (G.J. Morriello).
https://doi.org/10.1016/j.bmcl.2021.128082
Received 18 December 2020; Received in revised form 23 April 2021; Accepted 28 April 2021
Available online 13 May 2021
0
960-894X/© 2021 Elsevier Ltd. All rights reserved.

G.J. Morriello et al.
Bioorganic & Medicinal Chemistry Letters 44 (2021) 128082
O
N
O
and 8. Hydrogenation of 7 and 8 using 10% Pd on carbon as catalyst
yielded compounds 9 and 10, respectively.
MeO
N
MeO
MeO
HN
N
These initial analogs were evaluated in an in vitro PDE2 binding assay
as well as countered screened versus PDE1 and PDE3-11. This initial
data set is summarized in Table 1. Gratifyingly, the simple racemic H
derivative, 9, demonstrated promising PDE2 activity albeit with poor
PDE-selectivity. The olefin compound 7 demonstrated a dramatic loss in
PDE2 potency, consistent with observations in the parent pyrazolopyr-
imidone series.16 Simple alkylation of the pyrazole N1 nitrogen led to
compound 10 which demonstrated a loss in PDE2 activity as well as
selectivity compared to 9. The two enantiomers of compound 9 were
separated by chiral SFC to yield 11 and 11-ent. While compound 11
possessed a similar profile to 9, it was clear that it would be necessary to
separate any racemic compound for accurate potency and selectivity
determination moving forward due to the preference for one enantiomer
around the benzylic site over the other.
N
N
OH
NH2
ND-7001
Bay 60-7550
O
O
Cl
N
N
HN
N
O
OCF3
F
N
N
N
HN
O
O
An X-ray co-crystal of 11 (Fig. 3) with PDE2A, revealed key in-
teractions with active-site water molecules. The early hypothesis is that
enantiomer 11-ent would direct the aromatic moiety away from the
hydrophobic pocket and most likely disrupt or displace one of the crucial
water interactions causing a>10-fold loss in potency.
O
CF3
TAK-915
Janssen
HO
O
N
N
N
NH
Based upon the promising results in Table 1 and the X-ray of com-
pound 11, efforts shifted towards the preparation of analogs bearing
additional hydrogen-bonding capabilities. This design was meant to test
the specific hypothesis around interactions with a non-conserved
glutamine, Gln 812, which would be expected to enhance both po-
tency and PDE-selectivity. As seen in Fig. 3, the compound forms a
bidendate hydrogen bond with Gln 859 which positions the compound
to have an interaction with Gln 812 through water which leads to
increased PDE2 selectivity. Our hypothesis resided in the thought that
increased direct interactions with Gln 812 via a direct hydrogen bonding
interaction would lead to enhanced selectivity. Several methods that
were employed to achieve this are shown in Schemes 2 and 3. Com-
pound 5 could be treated with various primary bromides in the presence
N
N
N
N
N
N
CF3
N
N
Pfizer
Pfizer
N
9
–14
Fig. 1. Reported PDE2 inhibitors.
R
R
2 3
of K CO to afford the N-alkylated cores (Scheme 2). Treatment under
R1
R1
modified Suzuki coupling conditions using a Buchwald APhos-Pd-G3
catalyst and a vinyl boronate afforded the corresponding vinyl de-
rivatives 14 and 15. Hydrogenation using 10% Pd on carbon afforded
the racemic mixture which was separated into the enantiopure final
compounds using SFC separation in Scheme 2.
N
N
N
N
N
HN
HN
N
R2
R2
O
O
B
A
An alternative preparation of the N-alkylated derivatives could be
achieved by treatment of compound 9 with a primary halide in the
Fig. 2. Markush example of the “flipped” pyrazole ring.
presence of K
Scheme 3.
2 3
CO to afford the final compounds 17 and 19 shown in
R
Br
N
Table 2 summarizes the SAR data for the additional linked de-
rivatives from Schemes 2 and 3. Extension to an N-ethanol linker pro-
vided compound 16 which demonstrated excellent activity for PDE2
while maintaining over 450-fold selectivity versus the other PDE’s
tested. The enantiomeric derivative 16-ent lost over an order of
N
N
O
N
N
a
b
N
R
O
HN
N
HN
N
NH2
O
R
O
5:
6
1
2
: R = H
: R = Me
3: R = H
4: R = Me
=
=
R
H
: R Me
Table 1
F3C
HN
F3C
HN
In vitro profiles of pyrazolopyrimidione derivatives 7,9–11.
N
O
c
N
O
d
N
N
N
N
R
R
a
: R = H
8
9
: R = H
1
0: R = Me
Compd
R
hPDE2 Ki (nM)
hPDEx1-11 selctivity
7
: R = Me
9
7
H
27
>20
nt
H
2360
70
◦
Scheme 1. (a) benzyl ethanimidiothioate hydrochloride, pyridine, 115 C; (b)
1
0
Me
H
>9
>22
nt
′
′′
NBS, CH
3
CN; (c) vinyl boronate, Pd(OAc)
2
, sodium 3,3 ,3 -phosphinetriyl-
O; (d) H (balloon), 10% Pd/
11
15
tribenzenesulfonate hydrate, DIPEA, DMF/H
C, EtOH.
2
2
11-ent
H
293
a
Values are the mean of two (n = 2) runs. See Supporting Information for
.
b
assay details nt = not tested.
2

G.J. Morriello et al.
Bioorganic & Medicinal Chemistry Letters 44 (2021) 128082
Table 2
In vitro profiles of pyrazolopyrimidione derivatives 11, 16-19.
a
Compd
R
PDE2 Ki (nM)
hPDEx1-11 selctivity
1
1
1
1
H
H
15
>22
b
1-ent
293
1.7
nt
6
>480
1
6-ent
64.7
>13
1
1
7
1.8
>350
>13
Fig. 3. X-ray crystal structure of compound 11 bound to PDE2.
7-ent
26.8
1
8
7.0
>130
Br
N
N
R
Br
N
N
O
N
O
b
a
b
18-ent
178
324
nt
HN
HN
b
N
19
nt
H
5
=
2: R CH CH OBn
2 2
1
1
b
1
9-ent
521
nt
=
3: R CH CF
2
3
CF3
CF3
a
Values are the mean of two (n = 2) runs. See Supporting Information for all
b
assay details. nt = not tested.
*
N
the trifluoropropyl derivatives, 19 and 19-ent, showed very poor PDE2
activity shown in Table 2. As can be seen, PDE2 potency starts drifting as
bulkier substituents and longer chain lengths are added. This loss in
potency may be due to steric clashes of the larger substituents in the
narrow pocket between Leu 809 and Gln 812. Also, the longer chain puts
the substituent too far away from the important direct interact with Gln
N
O
c, d
=
6: R CH CH OH
2 2
1
N
N
HN
18: R = CH CF3
HN
2
N
N
R
R
O
=
4: R CH CH OBn
2 2
=
5: R CH CF3
2
1
1
8
12 which would also cause deterioration of the PDE2 potency.Table 3.
As it was evident that an additional hydrogen bonding moiety in
◦
Scheme 2. (a) BrCH
2
CH
2
OBn or BrCH
2
CF
3
, K
◦
2
CO
3
, 75 C, DMF; (b) vinyl
between the inhibitor and Gln 812 enhanced PDE2 selectivity, efforts
were then focused on the two optimal N-substituents: the terminal fluoro
and hydroxyl moieties. Hydroxy ethyl and fluoro ethyl were chosen as
the N1 substituent with the highest potential to participate in this
additional interaction with Gln 812. Keeping these two N1 substituents
constant we also sought to investigate SAR around the benzylic phenyl
ring and an appropriate synthetic route was designed to accommodate
these plans.
boronate, Aphos Pd G3, 1 M K
EtOH; (d) SFC separation.
3
PO
4
, NMP, 80 C; (c) H
2
(balloon), 10% Pd/C,
CF3
CF3
*
As seen in Scheme 4, the starting bromo intermediate was first
alkylated with 2-benzoloxy-1-bromoethane to enable access to both the
hydroxyl and fluoro analogs from a common intermediate. Heck reac-
tion of 12 with 1-(ethyloxy)butane in ethylene glycol afforded a vinyl
ether, which upon treatment with 2 M HCl gave ketone 20. The ketone
was then treated with either an aryl Grignard or an aryllithium reagent,
to provide the substituted tertiary aryl alcohol. Elimination with Burgess
reagent then afforded olefin 21. Reduction of the double bond with
concomitant removal of the benzyl protecting group could be achieved
N
N
a,
b
N
N
N
HN
HN
N
H
O
R
O
9
17 R = CH F
2
=
1
9 R CH CF
2
3
◦
Scheme 3. (a) BrCH
2
CF
3
or BrCH
2
CH
2
CF
3
,
K
2
CO
3
,
75 C, DMF; (b)
SFC separation.
2
with 10% Pd/C in ethanol under an atmosphere of H . This racemic
mixture was then be separated via chiral HPLC to give compounds
magnitude in activity versus PDE2 in addition to exhibiting a serious
erosion in selectivity versus the other PDE’s (>13 only). Interestingly,
the ethyl fluoro derivatives, 17 and 17-ent, showed very similar trends
with the former compound possessing a good balance of PDE2 potency
and selectivity (Table 2). The trifluoroethyl derivative 18 demonstrated
reasonable PDE2 activity coupled with reduced selectivity for PDE2
2
2–24. Lastly, manipulation of the alcohol of the active enantiomers
with DAST afforded fluoroethyl targets 25 and 26.
Gratifyingly, >1000-fold selectivity was achieved by the introduc-
tion of a hydrogen-bond donating hydroxyl group forming an additional
direct interaction with Gln 812. When comparing the two sub-series, it is
apparent that hydroxyl substituted compounds 22 and 24 are more
sensitive to arene substitution than their matched-pair fluoro analogs 25
(
>130) while the enantiomer was not of interest. Interestingly, both of
3

G.J. Morriello et al.
Bioorganic & Medicinal Chemistry Letters 44 (2021) 128082
Table 3
O
Br
N
N
N
O
c, d
a, b
In vitro profiles of pyrazolopyrimidione derivatives 22–26.
N
R
HN
HN
N
N
O
a
Compd
R
R
1
PDE2 Ki (nM)
1.1
hPDEx1-11 selctivity
12
2
0
OBn
2
2
>1500
R
R
2
2
3
4
208
2.6
–
H
N
N
O
e, f
g
>2000
N
N
HN
HN
N
N
O
OBn
OH
21
22-24
2
2
5
6
0.92
1.3
>500
>500
R
H
N
N
HN
N
a
Values are the mean of two (n = 2) runs. See Supporting Information for all
O
b
assay details. nt = not tested.
F
2
5-26
and 26. In contrast, comparison of the para-CF
3
compounds 16 and 17 to
analogs
Scheme 4. (a) 1-(ethenyloxy)butane, DPPP, Pd(OAc)
2
, Et
3
N, ethylene glycol,
their matched pair containing para-t-butyl and meta-F, para-CF
3
◦
◦
1
45 C; (b) 2 M HCl, THF, rt; (c), ArLi or ArMgBr, THF, ꢀ 78 C; (d) Burgess
◦
in the fluoro containing sub-series, minimal selectivity differences were
observed (>350 for 17 vs > 500 for both 25, 26 respectively). As for the
hydroxyl containing compounds, a gain of 2- to 4-fold increased selec-
tivity is observed with the analogous substitutions on the phenyl ring
reagent, toluene, 110 C: (e) H (balloon), 10% Pd/C, EtOH; (f) Chiral HPLC or
2
2 2
SFC separation; (g) DAST, CH Cl , rt.
(
>480 for 16 vs > 1000 and > 2000 for 22, 24 respectively). One
explanation for this increase in selectivity might be the better Vander-
waal interactions of the aromatic ring in the hydrophobic pocket (Ile 870
and Thr 850 residues) caused by extensive water networking with key
parts of the PDE2 active site. (Fig. 4 and 5) As seen in Fig. 4, the hydroxyl
substituent interaction with the non-conserved Gln812 side chain pro-
vides a rationale for enhanced selectivity.
Since compounds 22 and 26 displayed the best affinity for PDE2 and
acceptable selectivity over the other PDE family members, they were
both further profiled for their pharmacokinetic properties. In both Ta-
bles 4 and 5, a combined heat map and data record was added to help
visualize the selectivity versus the other PDE isoforms to which green is
>
500 fold selectivity, orange is between 100 and 500 fold and red is <
1
00 fold compared to their PDE2 potency. Compound 22 showed
promising overall properties with a good rat Pharmacokinetic (PK)
profile with moderate clearance and 3 h effective half-life, and also
excellent selectivity on the ancillary targets (CYPs, ion channels, PXR).
Compound 22 also displayed good kinetic solubility (pH = 7; 117
μ
M,
Fig. 4. X-ray crystal structure of compound 24 bound to PDE2.
FASSIF: 148
μ
M) and good passive permeability (Papp = 29.5). How-
ever, the polarity of the hydroxyl group resulted in an higher Pgp efflux
ratio in both rat and human cell lines (AB:BA ratio 18.7 rat; 3.3 human).
Although, in silico predictions of brain penetration potential, .i.e. CNS
probabilistic Multiparameter Optimization (pMPO) and rat Pgp were in
a favorable range (0.77 and AB:BA predicted ratio 3.2, respectively),
experimental Pgp efflux ratios were observed to be significantly higher
than the predicted values limiting consideration of these compounds for
further advancement. The fluoro analog 26 was also predicted to have
favorable in silico brain penetration properties (CNS pMPO: 0.76, Pgp:
structure, it was hoped it would have reduced susceptibility to act as a
Pgp efflux substrate. This was confirmed experimentally and compound
26 was found not to be a substrate for Pgp efflux; 1.3 respectively. In
addition to that, CNS penetration potential of compound 26 displayed
good cell permeability, and a relatively clean ancillary profile, with
good FASSIF solubility (177 M) and as such was chosen for additional
μ
profiling in in vivo pharmacokinetic studies. Unfortunately, compound
26 exhibited high plasma clearence and a relatively short half-life of 0.8
h in rat. Efforts to optimize pharmacokinetic profile of this series will be
1
.0) but since 26 has one less hydrogen bond donor and acceptor in the
4

G.J. Morriello et al.
Bioorganic & Medicinal Chemistry Letters 44 (2021) 128082
Table 5
Full physicochemical summary of compound 26.
PDE 2-h IC50: 1.3 nM
PDE(1-11) selectivity:
PDE:
M:
1
3
4
5
6
7
8
9
10
11
μ
> 60
5.7
3.3
21
11
> 75
>50
> 50
5.8
0.6
Pharmacokinetics
rat
Kinetic Solubility
rat ( M)
μ
Clp: (ml/min/kg)
t1/2: (h)
49
pH 2
60
Fig. 5. X-ray crystal structure of compound 26 bound to PDE2.
1.4
0.8
FASSIF
pH 7
177
20
MRT: (h)
Table 4
Pgp efflux
Metabolic stability
Rat BA/AB ratio
1.4
Hum heps
Rat heps
Int Cl: 16.4
Int Cl: 54.2
Human BA/AB ratio
Control
0.6
0.7
Full physicochemical summary of compound 22.
Ancillary activity
CYP inhibition
PPB (F
u
)
Rat
1.4%
1.6%
0.9%
2
3
2
D6
A4
C9
>50
μ
μ
μ
M
M
M
Rhesus
Human
>50
>50
PDE 2-h IC50: 1.1 nM
PDE(1-11) selectivity:
Ion Channels
hPXR
17–30
45%@10 M
μM
μ
PDE:
M:
1
3
4
5
6
7
8
9
10
18
11
compounds which were profiled for pharmacokinetic properties. Com-
pounds 22 and 26 both demonstrated excellent PDE2 potency (1.1 and
1.3 nM respectively) and PDE-family selectivity (>400 fold), good cell
permeability, and favorable ancillary target profiles. Additionally,
compound 26 proved to fit most of the set criteria to commit to future
ongoing studies to access its potential for further development.
μ
> 60
1.8
3.5
23
27
> 75
> 50
> 50
6.2
Pharmacokinetics
Rat
Kinetic Solubility
rat ( M)
μ
Clp: (ml/min/kg) 24
t1/2: (h)
24
pH 2
117
3.1
2.5
FASSIF
pH 7
148
115
MRT: (h)
Pgp efflux
Metabolic stability
Declaration of Competing Interest
Rat BA/AB ratio
Human BA/AB ratio
Control
18.7
3.3
Hum heps
Rat hep
Int Cl: 11.4
Int Cl: 137.4
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
0.8
Ancillary activity
CYP inhibition
PPB (F
u
)
Rat
4.9%
3.5%
3.0%
Acknowledgment
2D6
3A4
2C9
>50
44
>50
9.6–30
16%@10
μ
M
Rhesus
Human
μ
M
The authors would like to thank Santhosh Neelamkavil for his helpful
review and insights.
μM
Ion Channels
hPXR
μ
M
μ
M
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Bioorganic & Medicinal Chemistry Letters 44 (2021) 128082
1
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1
4 Other Pfizer core: (a) Plummer, M. S.; Cornicelli, J.; Roark, H.; Skalitzky, D. J.;
Stankovic, C. J.; Bove, S.; Pandit, J.; Goodman, A.; Hicks, J.; Shahripour, A.; Beidler,
6