Synthesis and in vitro biological evaluation of pyrazole group-containing analogues for PDE10A

Article abstract of DOI:10.1039/c2md20239e

Twenty eight new analogues were synthesized by optimizing the structure of MP-10 and their in vitro binding affinities towards PDE10A, PDE3A/B, and PDE4A/B were determined. Among these new analogues, 10a, 10b, 10d, 11a, 11b and 11d are very potent towards PDE10A and have IC₅₀ values of 0.40 ± 0.02, 0.28 ± 0.06, 1.82 ± 0.25, 0.24 ± 0.05, 0.36 ± 0.03 and 1.78 ± 0.03 nM respectively; these six compounds displayed high selectivity for PDE10A versus PDE3A/3B/4A/4B. The promising compounds will be further validated in vivo to identify PDE10A imaging tracers. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2md20239e

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Synthesis and in vitro biological evaluation of pyrazole
group-containing analogues for PDE10A†
Cite this: Med. Chem. Commun., 2013,
4, 443
*
Junfeng Li, Hongjun Jin, Haiying Zhou, Justin Rothfuss and Zhude Tu
Twenty eight new analogues were synthesized by optimizing the structure of MP-10 and their in vitro
binding affinities towards PDE10A, PDE3A/B, and PDE4A/B were determined. Among these new
analogues, 10a, 10b, 10d, 11a, 11b and 11d are very potent towards PDE10A and have IC50 values of
0.40 ꢀ 0.02, 0.28 ꢀ 0.06, 1.82 ꢀ 0.25, 0.24 ꢀ 0.05, 0.36 ꢀ 0.03 and 1.78 ꢀ 0.03 nM respectively; these
six compounds displayed high selectivity for PDE10A versus PDE3A/3B/4A/4B. The promising
compounds will be further validated in vivo to identify PDE10A imaging tracers.
Received 11th August 2012
Accepted 10th December 2012
DOI: 10.1039/c2md20239e
www.rsc.org/medchemcomm
striatum of engineered PDE10A knocked out mice; this provided
more evidence that the PDE10A enzyme is a promising thera-
Introduction
Phosphodiesterase 10A (PDE10A) is one of the 11 families of
phosphodiesterase enzymes. PDE10A is a unique dual specicity
enzyme; it is able to hydrolyze cyclic adenosine monophosphate
(cAMP) and cyclic guanosine monophosphate (cGMP) to inactive
adenosine monophosphate (AMP) and guanosine mono-
phosphate GMP, respectively.1,2 PDE10A was identied inde-
pendently by three groups in 1999 (ref. 2–4) and has the most
unique expression with mRNA levels in the brain and testis.3
Within the brain, the highest expression of PDE10A protein is in
the medium spiny neurons of the striatum (caudate and puta-
men), nucleus accumbens, and olfactory tubercle of mice, dogs,
cynomolgus andhumans.5 Due tothe unique striatallocalization
of PDE10A and the function of PDE10A in the brain, inhibition of
PDE10A represents a novel approach for treating neurological
and psychiatric disorders such as schizophrenia, Parkinson's
disease, and Huntington's disease (HD);6–8 this therapeutic
approach may avoid unwanted side effects such as extrapyra-
midal symptoms of conventional therapeutics. For example,
investigating the levels of PDE10A in the brain of patients with
Huntington's disease indicated that the level of PDE10A protein
was decreased compared to that of age-matched healthy
individuals;9 aer treating with PDE10Ainhibitor, 2-[4-[pyridin-4-
yl-1-(2,2,2-triuoroethyl)-1H-pyrazol-3-yl]-phenoxymethyl]-quin-
oline (TP-10), an analogue of 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-
pyrazol-3-yl)phenoxy)-methyl)quinoline (MP-10) (Fig. 1), both
neuropathology and symptoms in R6/2 mice were ameliorated;
the behavioural symptoms of R6/2 mice, such as rotarod
performance, were improved.10 In addition, chronically treating
with TP-10 resulted in changes in gene expression11 in the
peutic target for psychotic and related neurodegenerative
diseases.
Positron emission tomography (PET) provides a unique and
novel non-invasive imaging tool to investigate the changes in
levels of PDE10A in the brain of living subjects and to study the
physiological function of PDE10A in the central nervous system
(CNS). Investigators have made signicant efforts to identify a
clinically suitable PET probe for imaging the changes in levels
of PDE10A in the human brain.8,12–14 In recent years, [11C]-
papaverine and other radioligands were evaluated in vivo.15–20
However, due to the lack of suitable radiopharmaceutical
properties of the reported radiotracers,15–20 the evaluation of
PDE10A PET tracers is still in process. To date, no clinically
suitable PET tracer was reported. Among the reported PET
radiotracers, substituted pyrazole-containing ligands radio-
labeled by introducing carbon-11, or uorine-18 via N-alkylation
of the pyrazole ring had attracted more attention16,18,19 because
of the use of MP-10 as a PDE10A inhibitor in clinical trials for
treatment of schizophrenia;21 PET radiotracers, [11C]MP-10, 18F-
JNJ41510417, [18F]1, [18F]2 shown in Fig. 1, were made by
introducing the
[
11C]methyl, [18F]uoroethyl or [18F]uo-
ropropyl group on the N-atom of the pyrazole scaffold and
further evaluated in vivo in rodents and monkeys.16,18,19,22 Our
group had reported that the in vivo microPET studies of [11C]
MP-10 in monkeys showed a very clear anatomic structure of
monkey brain and the highest accumulation of radioactivity in
the striatal area of the brain, higher target-to-non-target ratios,
but the kinetics displayed an increasing trend post-injection of
[
11C]MP-10. Further metabolite analysis of monkey plasma,
rodent plasma and brain tissues revealed that the radioactive
metabolite formed post-injection of radiotracer [11C]MP-10 by
O-dealkylation of [11C]MP-10 in vivo; this radioactive metabolite
was able to cross the blood–brain-barrier and accumulate in the
brain; radioactivity of the radioactive metabolite in the brain
Department of Radiology, Washington University School of Medicine, St. Louis, MO,
63110, USA. E-mail: tuz@mir.wustl.edu; Fax: +1-314-262-8555; Tel: +1-314-362-8487
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c2md20239e
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Fig. 1 Structures of [11C]papaverine, TP-10 and its C-11 or F-18 labeled analogue radiotracers.
may lead to misinterpretation of the measurement of PDE10A
The syntheses of several MP-10 analogues were achieved by a
levels in the brain. Thus, further optimization of the pyrazole- Mitsunobu reaction of heteroaromatic benzyl alcohols with 6 as
containing analogues to overcome the radioactive metabolite an alkylating agent.21 Attempts to synthesize compounds 10a–f
concern is imperative.
and 11a–f were very challenging due to similar retention factor
In our current studies, we had taken the following strategies values (Rf) of intermediates quinolin-2-yl-methanol and the
to design the new analogues to overcome the radioactive nal compounds 10a–f and 11a–f. To overcome this challenge,
metabolite concern: (1) introducing a methoxy into a quinon- an alternative approach was taken; substituted phenols 6 or 7
line fragment of the MP-10 structure, which creates a new were coupled with substituted 2-bromomethylquinolines 9a–f
position to label with carbon-11; we expect that the new radio- to afford target compounds for which the purication was easily
active metabolite obtained from the substituted 2-methyl- achieved by column chromatography. Synthesis of target
quinoline fragment via O-dealkylation of phenyl ether does not compounds began with commercially available 4-(benzyloxy)
have the capability to cross the blood–brain-barrier (BBB) and benzoic acid (3). Following the literature procedure,21
enter into the brain; (2) replacing the oxygen (O) atom that links compounds 4 and 5 were afforded in three steps. Debenzylation
the substituted methylquinoline fragment and the substituted of compounds 4 and 5 afforded substituted phenols 6 and 7.
pyrazole fragment of MP-10 with a nitrogen (N) or sulfur (S) Commercially unavailable 4-methoxy-2-methylquinoline (8b)
atom; we expect that the new derivatives in which the N or S was synthesized by treating 4-chlorine-2-methylquinoline with
serves as a linkage atom will be more stable. This may increase sodium methoxide (NaOCH3);23,24 8-methoxy-2-methylquinoline
the metabolic stability of radiotracers in vivo or form new (8f) was synthesized via O-alkylation of 2-methylquinolin-8-ol
radioactive metabolites that do not enter into the brain and with iodomethane in dimethylformamide (DMF). Methoxy-2-
accumulate in the striatal area and other regions. In the current bromomethylquinolines 9a–f were synthesized by bromination
manuscript, we reported our efforts on synthesizing the new of methoxy substituted 2-methylquinolines 8a–f using N-bro-
analogues based on the above design strategies and their in vitro mosuccinimide (NBS). O-Alkylation of phenols 6 or 7 with
binding affinity evaluation.
substituted
2-bromomethylquinolines
9a–f
afforded
compounds 10a–f or 11a–f respectively, following the literature
procedure with minor modication.21,25
The syntheses of the S-atom bridged analogues 10g–j and
11g–j were achieved according to Scheme 2. Synthesis began by
reacting 4-bromobenzoic acid 12 with N,O-dimethylhydroxyl-
amine hydrochloride and 1,1-carbonyldiimidazole (CDI) to
Results and discussion
Chemistry
The syntheses of compounds 10a–f and 11a–f were accom-
plished according to Scheme 1.
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Scheme 1 Synthesis of compounds 10a–f and 11a–f. Reagents and conditions: (a) CDI, N,O-dimethylhydroxylamine hydrochloride, NEt3, CH2Cl2, rt; (b) 4-picoline, LDA,
ꢁ78 ꢂC to rt; (c) N,N-dimethylformamide-dimethyl acetal, reflux, then methylhydrazine; (d) H2, Pd/C, ethanol/EtOAc; (e) NBS, AIBN, CCl4, reflux; (f) NaH, DMF, rt.
afford Weinreb amide 13 in nearly quantitative yield. Treatment introducing the methoxy group is to provide a new position for
of 4-picoline with lithium diisopropyl amide (LDA) at ꢁ78 ꢂC introducing the [11C]methoxy group if the new analogues have
followed by adding this solution to the solution of 13 in tetra- high binding affinity and selectivity for PDE10A. To test this
hydrofuran (THF) afforded compound 14. Treatment of strategy, we rst synthesized compounds 10b, 10d–f and their
compound 14 with dimethoxymethyl-dimethyl amine afforded regioisomers 11b, 11d–f by introducing the methoxy group at
the key intermediate enaminones 15 and 16. Compounds 15 or the 4, 6, 7 and 8 positions of the quinoline fragment. The in vitro
16 upon treatment with sodium thiomethoxide in dimethyla- PDE10A binding affinity data of compounds 10b, 10d–f dis-
cetamide (DMA) at high temperature afforded intermediates 17 played the decreasing order as: 4-methoxy > 6-methoxy > 7-
or 18 respectively. Coupling of thiophenols 17 or 18 with methoxy z 8-methoxy; the IC50 values (nM) of 10b and 10d–f
substituted 2-bromomethylquinolines 9b, 9d–f afforded thio- were 0.28 ꢀ 0.06, 1.82 ꢀ 0.25, 46.0 ꢀ 6, and 41.5 ꢀ 6.5 nM
ether analogues 10g–j or 11g–j.
respectively. Among compounds 10b, 10d–f, compounds 10b
The syntheses of the N-atom bridged analogues 10k–n and and 10d are very potent for PDE10A, particularly, for 10b, the in
11k–n were achieved according to Scheme 3. The Gabriel vitro IC50 value reached 0.28 nM.
synthesis procedure26–28 was followed by treating the aromatic
To extend our structural modication studies, the regioiso-
bromides 15 or 16 with potassium phthalimide to afford the meric counterparts 11b, 11d–f were also synthesized and their
corresponding N-alkylphthalimide 19 or 21. Treating 19 or 21 in vitro binding affinities were determined as shown in Table 1.
with ethanolic hydrazine following the Ing–Manske procedure29 The in vitro data suggested that compounds 11b, 11d–f and
afforded aromatic amines 20 or 22. N-Alkylation of the aromatic compounds 10b, 10d–f have similar decreasing binding affinity
amines 20 or 22 with substituted 2-bromomethylquinolines 9b, order; for compounds 11b, 11d, 11e, and 11f, the IC50 values (nM)
9d–f afforded the desired N-atom bridged analogues 10k–n or were 0.36 ꢀ 0.03, 1.78 ꢀ 0.03, 95 ꢀ 15, and 199 ꢀ 21 nM;
11k–n.
4-methoxy substituted compound 11b, similar to its counterpart
10b, has the highest binding affinity for PDE10A. The next most
potent compound is the 6-methoxy substituted 11d. Compounds
10b and 11b had similar subnanomolar affinities (0.1 nM < IC50
Biological binding studies
We explored the structure of MP-10 by introducing the methoxy values < 0.5 nM). However, for the less potent compounds 11e
group into the quinoline fragment of the MP-10. The strategy of and 11f, the IC50 values revealed that the 8-methoxy substituted
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Scheme 2 Synthesis of compounds 10g–j and 11g–j. Reagents and conditions: (a) CDI, N,O-dimethylhydroxylamine hydrochloride, NEt3, CH2Cl2, rt; (b) 4-picoline, LDA,
ꢁ78 ꢂC to rt; (c) N,N-dimethylformamide-dimethyl acetal, reflux, then NH2NHCH3; (d) NaSMe, DMA, 150 ꢂC; (e) substituted 2-bromomethylquinoline, NaH, DMF, 0 ꢂC to
rt, overnight.
11f (199 nM) has a 2-fold higher IC50 value than that the MP-10 was able to retain the high PDE10A binding affinity.
7-methoxy substituted compound 11e (95 nM).
Thus, we further explored the structure of MP-10 by replace-
From the above structure–activity relationship analysis, we ment of the O-atom link bridge with a N-atom or S-atom. For the
concluded that introduction of a methoxy group at an appro- S-atom bridged analogues, compounds 10g–j and 11g–j
priate position of the quinoline fragment in the structure of were synthesized; for the N-atom bridged analogues, 10k–n and
Scheme 3 Synthesis of compounds 10k–n and 11k–n. Reagents and conditions: (a) potassium phthalimide, Cul, DMA, 150 ꢂC; (b) hydrazine hydrate, EtOH, reflux;
(c) substituted 2-bromomethylquinoline, Na2CO3, acetonitrile, 80 ꢂC.
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Table 1 PDE10A affinities of new analoguesa
IC50 value (nM)
PDE10A
IC50 value (nM)
Compd
X
R1
Log Db
Compd
X
R1
PDE10A
Log Db
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
O
O
O
O
O
O
S
S
S
S
3-OMe
4-OMe
5-OMe
6-OMe
7-OMe
8-OMe
4-OMe
6-OMe
7-OMe
8-OMe
4-OMe
6-OMe
7-OMe
8-OMe
0.40 ꢀ 0.02
3.87
3.79
3.92
3.61
3.77
3.28
3.89
3.72
3.88
3.39
3.52
3.36
3.52
3.02
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
O
O
O
O
O
O
S
S
S
S
3-OMe
4-OMe
5-OMe
6-OMe
7-OMe
8-OMe
4-OMe
6-OMe
7-OMe
8-OMe
4-OMe
6-OMe
7-OMe
8-OMe
0.24 ꢀ 0.05
0.36 ꢀ 0.03
81.4 ꢀ 9.2
1.78 ꢀ 0.03
95 ꢀ 15
3.87
3.79
3.92
3.61
3.77
3.28
3.89
3.72
3.88
3.39
3.52
3.36
3.52
3.02
0.28 ꢀ 0.06
60 ꢀ 26
1.82 ꢀ 0.25
46 ꢀ 6
41.5 ꢀ 6.5
168 ꢀ 52
199 ꢀ 21
1850 ꢀ 450
610 ꢀ 80
415 ꢀ 65
400 ꢀ 60
635 ꢀ 55
635 ꢀ 15
3050 ꢀ 450
645 ꢀ 255
4250 ꢀ 650
5150 ꢀ 250
4600 ꢀ 400
N
N
N
N
13 900 ꢀ 1100
7500 ꢀ 700
7400 ꢀ 600
10 900 ꢀ 700
N
N
N
N
a
IC50 is dened as the concentration of the inhibitor required to reduce the [3H]cAMP hydrolysis activity of recombinant human PED10A by 50%
with scintillation proximity assay. b Calculated value at pH ¼ 7.4 by ACD/I-Lab ver. 7.0 (Advanced Chemistry Development, Inc., Canada).
11k–n were synthesized. Our in vitro data revealed: (1) PDE10A enzyme. We further synthesized 10a, 10c, 11a, and
compounds 10g–j, containing a 4-(1-methyl-4-(pyridin-4-yl)-1H- 11c by introducing the methoxy group at 3 and 5 positions
pyrazol-5-yl)phenyl fragment, had higher affinity than their of the quinoline fragment; the in vitro data suggested that
corresponding isomers 11g–j, containing a 4-(1-methyl-4-(pyr- 3-methoxy substituted compounds 10a and 11a were very
idin-4-yl)-1H-pyrazol-3-yl)phenyl fragment; this observation was potent for PDE10A and the IC50 values are 0.40 ꢀ 0.02 and
similar to the results of the O-atom bridged analogues 10b, 10d– 0.24
ꢀ
0.05 nM, which had similar PDE10A binding
f versus 11b, 11d–f; (2) even the S-atom bridged analogues 10g–j potency to that of the 4-methoxy substituted compounds,
displayed higher binding affinity than that N-atom bridged 10b and 11b. However, 5-methoxy substituted compounds
analogues 10k–n, and the binding affinity of methoxy 10c and 11c displayed lower PDE10A binding affinities;
substituted analogues displayed the order as: 4-methoxy > 6- the IC50 values were 60 ꢀ 26 nM for 10c and 81.4 ꢀ 9.2 nM
methoxy z 7-methoxy > 8-methoxy, for which the IC50 values for 11c.
are 168 ꢀ 52, 415 ꢀ 65, 400 ꢀ 60, 635 ꢀ 15 nM for compounds
Inhibition of PDE3A/B could lead to arrhythmia and
10g–j respectively. The PDE10A binding affinities of S-atom increased mortality,30,31 and the role of phosphodiesterase 4
bridged analogues 10g–j were much lower than those of their could be a regulator of central nervous system function and
corresponding O-atom bridged analogues 10b, 10d–f. Among 16 inhibition of PDE4A could increase heart and respiratory
compounds 10g–n and 11g–n containing either S-atom or N- rates.32 The binding affinities of compounds 10a, 10b, 10d,
atom bridge, the most potent compound 10g had the IC50 value 11a, 11b, and 11d, which have IC50 values less than 5 nM for
of 168 ꢀ 52 nM, which was 600-fold less potent than that of 10b PDE10A, were further evaluated in vitro for PDE3A/B and
(0.28 ꢀ 0.06 nM), the corresponding O-atom bridged analogue. PDE4A/B; the results are shown in Table 2. The in vitro
The binding affinities of N-atom link bridge analogues 10k–n data suggested that these six compounds had very weak
and 11k–n decreased dramatically (IC50 value > 645 nM). Thus, binding affinity for PDE3A/3B and PDE4A/4B with the IC50
replacing the O-atom bridge linkage with a S-atom or N-atom value > 1500 nM. This suggested that six compounds 10a, 10b,
did not generate PDE10A potent compounds.
10d, 11a, 11b and 11d not only had high potency for PDE10A
Based on above in vitro data, only the O-atom bridge but also had high selectivity for PDE10A versus PDE3A/3B and
linkage was able to retain the high binding potency for the 4A/4B.
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Table 2 PDE3A/B and PDE4A/B affinities of lead analogues
IC50 value (103 ꢃ nM)
NaOCH3
THF
TEA
Sodium methoxide;
Tetrahydrofuran;
Triethylamine;
Compd
PDE3A
PDE3B
PDE4A
PDE4B
TP-10
2-[4-[Pyridin-4-yl-1-(2,2,2-triuoro-ethyl)-1H-
pyrazol-3-yl]-phenoxymethyl]-quinoline.
10a
10b
10d
11a
11b
11d
123 ꢀ 21
27.5 ꢀ 2.5
78.0 ꢀ 4.0
18.7 ꢀ 3.1
29.0 ꢀ 4.0
1.50 ꢀ 0.50
82.7 ꢀ 10
3.85 ꢀ 0.23
2.56 ꢀ 0.11
3.37 ꢀ 0.18
199 ꢀ 16.0
4.18 ꢀ 0.33
5.60 ꢀ 0.52
3.43 ꢀ 0.21
1.79 ꢀ 0.10
2.56 ꢀ 0.09
31.5 ꢀ 3.60
5.06 ꢀ 0.40
7.10 ꢀ 0.58
3.85 ꢀ 0.95
9.75 ꢀ 1.25
16.9 ꢀ 2.1
4.80 ꢀ 1.20
3.00 ꢀ 0.14
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Conclusion
In the present study, we optimized the structure of MP-10 to
identify new compounds by introducing a methoxy group in the
quinoline fragment. The in vitro data suggested that six
compounds 10a, 10b, 10d, 11a, 11b, and 11d had high PDE10
binding potency with IC50 values of 0.40 ꢀ 0.02, 0.28 ꢀ 0.06,
1.82 ꢀ 0.25, 0.24 ꢀ 0.05, 0.36 ꢀ 0.03, and 1.78 ꢀ 0.03 nM
respectively. These six compounds also displayed high selec-
tivity for PDE10A against PDE3A/3B and PDE4A/4B with IC50
>
1500 nM. Aer further evaluating their PDE10A binding selec-
tivity against another PDE enzyme family, it is worthwhile to
label them with carbon-11 to conduct further in vivo validation.
However, optimizing the structure of MP-10 by replacing the
O-atom bridge with a S-atom or N-atom and introducing the
methoxy group into the quinoline fragment led to a dramatic
loss of the PDE10A binding affinities for the newly synthesized
analogues. These new analogues and their in vitro binding
affinities could provide helpful information for further struc-
ture–activity relationship studies.
Abbreviations
Anal.
BBB
CDI
Analysis;
Blood–brain-barrier;
1,1-Carbonyldiimidazole;
Central nervous system;
cyclic Adenosine monophosphate;
cyclic Guanosine monophosphate;
Dichloromethane;
N,N-Dimethylformamide;
Ethanol;
Ethyl acetate;
CNS
cAMP
cGMP
DCM
DMF
EtOH
EtOAc
HD
LDA
MeOH
MP-10
Huntington's disease;
Lithium diisopropyl amide;
Methanol;
2-((4-(1-Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)-
phenoxy)-methyl)quinolone;
N-Bromosuccinimide;
Phosphodiesterase 3A;
Phosphodiesterase 3B;
Phosphodiesterase 4A;
Phosphodiesterase 4B;
Phosphodiesterase 10A;
Positron emission tomography;
NBS
PDE3A
PDE3B
PDE4A
PDE4B
PDE10A
PET
448 | Med. Chem. Commun., 2013, 4, 443–449
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