Synthesis and in vitro characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.12.054

Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of PDE10A with IC₅₀ values ranging from 1.5 to 18.6 nM. Notably, the IC₅₀ values of compounds 26a, 26b, and 33c were 1.52 ± 0.18, 2.86 ± 0.10, and 3.73 ± 0.60 nM, respectively; these three compounds also showed high in vitro selectivity (>1000-fold) for PDE10A over PDE 3A/3B, PDE4A/4B. The high potency and selectivity of these three compounds suggests that they could be radiolabeled with PET radionuclides for further evaluation of their in vivo pharmacological behavior and ability to quantify PDE10A in the brain.

Full text of DOI:10.1016/j.bmcl.2014.12.054

Accepted Manuscript
Synthesis and in vitro characterization of cinnoline and benzimidazole ana-
logues as phosphodiesterase 10A inhibitors
Hao Yang, Francis N. Murigi, Zhijian Wang, Junfeng Li, Hongjun Jin, Zhude
Tu
PII:
S0960-894X(14)01362-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.12.054
BMCL 22299
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
13 November 2014
12 December 2014
15 December 2014
Please cite this article as: Yang, H., Murigi, F.N., Wang, Z., Li, J., Jin, H., Tu, Z., Synthesis and in vitro
characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors, Bioorganic &
Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.12.054
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Synthesis and in vitro characterization of cinnoline and benzimidazole analogues
as phosphodiesterase 10A inhibitors
Hao Yang a, Francis N. Murigi a, Zhijian Wang a, Junfeng Li a, Hongjun Jin a, Zhude Tu a, ∗
a Department of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors
were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A
inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of
PDE10A with IC50 values ranging from 1.5 to 18.6 nM. Notably, the IC50 values of compounds
26a, 26b, and 33c were 1.52 0.18, 2.86 0.10, and 3.73 0.60 nM, respectively; these three
compounds also showed high in vitro selectivity (> 1,000-fold) for PDE10A over PDE 3A/3B,
PDE4A/4B. The high potency and selectivity of these three compounds suggests that they could
be radiolabeled with PET radionuclides for further evaluation of their in vivo pharmacological
behavior and ability to quantify PDE10A in the brain.
Revised
Accepted
Available online
Keywords:
Benzimidazole analogues
Cinnoline analogues
Phosphodiesterase 10A
PET
2009 Elsevier Ltd. All rights reserved.
Phosphodiesterase 10A (PDE10A) is
a
dual specificity
correlation between PDE10A expression and clinical severity in a
recent exploratory study of 18F-JNJ42259152 in subjects with HD
and healthy controls,14 continued efforts to develop structurally
diverse PDE10A inhibitors may identify PET ligands with
improved in vivo pharmacological behavior. In this manuscript,
we report the synthesis and in vitro characterization of analogues
having either cinnoline (1) or benzimidazole (2) pharmacophores.
(Figure 1) Several new lead compounds reported here and a
previously reported cinnoline analogue have IC50 values < 20
nM. The diverse structures represented in these compounds may
result in the identification of tracers with kinetic and metabolic
profiles suitable for measuring PDE10A in the brain with PET.
enzyme that hydrolyzes both cyclic adenosine monophosphate
(cAMP) and cyclic guanosine monophosphate (cGMP) and is an
important modulator of intracellular levels of these cyclic
nucleotides. PDE10A has been cloned and characterized from
mouse and human tissue; it is highly expressed in striatum with
modest expression in other brain regions and low expression
outside the central nervous system (CNS).1-4 PDE 10A inhibitors
have been investigated as anti-psychotics in schizophrenia and
therapeutic agents for treating movement disorders associated
with Huntington’s disease and Parkinson disease and other
neurological disorders characterized by the decrease in the
activity of the neurons in the basal ganglia.5-7 Because positron
emission tomography (PET) imaging is a powerful non-invasive
tool for quantitatively measuring changes in CNS biomarkers
under baseline conditions and after treatment, a potent and
selective PDE10A tracer with suitable pharmacokinetic behavior
would be valuable in evaluating these therapeutic interventions.
11C-papaverine (IC50 = 36 nM)8, [11C]MP-10 (IC50 = 0.18 nM)
and structurally similar analogues have been investigated as PET
radiopharmaceuticals in rodents and nonhuman primates, though
pharmacokinetic properties and unfavorable metabolism limited
their utility in preclinical models of human disease.8-11 The MP-
10 analogue 18F-JNJ42259152 was approved for clinical
investigation in human subjects. Although preliminary data
showed promising kinetics in normal volunteers, the
development of kinetic models was challenging due to the
The syntheses of cinnoline PDE10A analogues 13a-d and
14a-b were accomplished according to Scheme 1. Commercially
available 1-(4-(benzyloxy)-3-methoxyphenyl)-ethanone (3) was
nitrated to afford compound 4, then reduced to give amine 6.
presence of brain-penetrating metabolites.12, 13 Despite the lack of
———
∗ Corresponding author. Tel.: +1-314-362-8487; fax: +1-314-362-8555;
E-mail address: tuz@mir.wustl.edu (Z. Tu).

Either 5, the commercially available 1-(2-amino-4, 5-
dimethoxyphenyl)ethanone or the amine underwent
synthesized. The IC50 values of 26b and 26e for PDE10A were
2.86 and 9.80 nM respectively, which are similar to the IC50
value we determined for 26a (1.52 nM). When the methoxyl
group at R1 in 26b was replaced by a benzyloxyl group in 26f,
the potency decreased with IC50 values increasing from 2.86 nM
for 26b to 350 nM for 26f. This result was consistent with the
results observed for 13a and 13b, 13c and 13d. When methoxyl
groups at R1 and R2 were either replaced by a cyclized group (-
OCH2O-) in 26c or removed in 26d, compounds 26c and 26d lost
inhibition activity for PDE10A completely. In comparing 26g
and 13c, when the –H group in R3 was substituted with a –Cl
group the potency of the inhibitor improved slightly from 14.0
nM for 13c to 5.52 nM for 26g. Compounds 26h and 26i were
obtained by replacing the methoxyl group of R1 in 26b with a
fluoroproxyl and 2-(oxymethyl)-quinloinyl group, respectively.
The IC50 values increased from 2.86 nM for 12b to 518 and 79.3
nM for 26h and 26i, respectively. This result is consistent with
the results observed for compounds 13a, 13b, 13c and 13d.
Throughout these measurements, the methoxyl group at R1
position of cinnoline structural analogues was critical in retaining
high potency for inhibiting PDE10A. The replacement of a
methoxyl group at R1 with other groups such as –H, -OCH2O-, -
6
diazotization/cyclization, followed by treatment with phosphorus
oxychloride to afforded intermediates 9 or 10, respectively. The
chloro intermediates were treated with 2-fluoro-3-substituted
boronic acid, followed by 4-substituted-4-piperidinol to give the
desired cinnoline PDE10A analogues 13a-d. The benzyl group in
compounds 13b or 13d was removed by using hydrogen under
10% Pd/C to afford hydroxyl containing compounds 14a or 14b.
Compounds 26a-i, which possess substitution groups in the
pyridine ring of cinnoline, were synthesized as shown in Scheme
2. Compound 26a was previously reported by Hu et al.15 The
synthesis of 26a-f and 26h-i used procedures similar to those
described above for 13a-b and 14a-b. The synthesis of
compound 26g was accomplished by the conversion of 4-
(pyridin-3-yl)piperidin-4-ol hydrochloride to compound 25 by
alkylation and Miyaura borylation, followed by Suzuki reaction
to afford the final product, 26g .
The syntheses of benzimidazole PDE10A analogues 33a-f
were accomplished according to Scheme 3. Treatment of
benzimidazole 27 with 4-methoxy benzoyl chloride under basic
conditions to generate compound 28, followed by N-methylation
of benzimidazole afforded compound 29. Deprotection of the
anisole with boron tribromide afforded phenol intermediate 30,
which was treated with 3-bromo-2-chloropyridine to give key
intermediate 31. Compounds 33a-c were obtained by Suzuki
coupling of intermediate 31 with substituted boronic acids.
Benzimidazole derivatives 33d-e were synthesized by two steps:
31 was first converted into the stannyl containing compound 32;
this was followed by Stille coupling of compound 32 with
substituted acyl chlorides to give compounds 33d-e.
OBn, fluoropropoxy, 2-(oxymethyl)-quinolinyl led to
a
significant reduction or a total loss in PDE10A inhibition
activity.
The benzimidazole analogues are structurally distinct from
cinnoline analogues; other benzimidazole inhibitors with high
potency toward PDE10A have been previously reported.18 Six
benzimidazole analogues (33a-f) were synthesized and their IC50
values for PDE10A were determined. In vitro data indicated that
compounds 33a, 33b, and 33c possessing
a phenyl, 4-
methoxyphenyl or heteroaryl substitution group for R1 had higher
inhibition potency for PDE10A; the IC50 values were 18.6 5.3,
8.0 1.38, and 3.73 0.60 nM for compounds 33a, 33b, and
33c, respectively. Optimization of the substituted group in R1
may improve potency for PDE10A. However, imposing a
carbonyl group between the aryl or heteroaryl group and the
skeleton of the benzimidazole resulted in significantly decreased
activity toward PDE10A. Both 33d and 33e lost inhibition
activity for PDE10A; the IC50 value of 33f increased to 1900 nM
as shown in Table 2.
In vitro assays were performed following standard literature
techniques developed by other investigators; the procedure used
here and in our prior studies is detailed in the supplementary
methods.7, 16 Briefly, a scintillation proximity assay (SPA) to was
used to measure the IC50 values of all inhibitors. The tritiated
cyclic nucleotide substrate concentration used in the enzyme
assay was 1/3 of the Km. The potency of each analogue as a PDE
inhibitor was determined by measuring the activity of a fixed
amount of recombinant human PDE enzyme in the presence of
varying inhibitor concentrations. After background subtraction,
counts for samples containing the inhibitors were plotted against
inhibitor concentration to calculate the IC50 values using non-
linear regression analysis. All compounds were independently
assayed at least three times.
Compounds 26a, 26b, and 33c are very potent inhibitors of
PDE10A with IC50 values < 5 nM, so further in vitro assays were
conducted to determine their selectivity. It has been reported that
inhibition of PDE3A/B may cause arrhythmia and increased
20
mortality,19,
inhibition of PDE4A may increase heart and
respiratory rates.21 Although such undesirable side-effects pose
fewer safety concerns for clinical radiotracers in comparison with
therapeutic agents, specificity is important. Therefore, the IC50
values of 26a, 26b and 33c for PDE3A, PDE3B, PDE4A, and
PDE4B were measured to determine their selectivity as PDE10A
inhibitors. The enzyme assays revealed that all three lead
compounds had very weak inhibition activity toward PDE3A/3B,
The IC50 values of the fifteen cinnoline analogues (13a-d,
14a-b, and 26a-i) and six benzimidazole analogues (33a-f) for
PDE10A are shown in Table 1 and Table 2. Among the
cinnoline analogues, for compounds 13a, 13b, and 14a, the
potency of substituted inhibitors for PDE10A showed in a
decreasing order OCH3> OBn > OH; the IC50 values of 13a, 13b,
and 14a were 18.4, 4,250, and 10,800 nM, respectively. Although
compounds 13c, 13d, and 14b have a pyridine-3-yl group instead
of a methyl group at the R3 position, a similarly decreasing trend
for PDE10A inhibition was observed for compounds 13c, 13d,
and 14b with IC50 values of 14, 1,550, and 6,620 nM,
respectively. The known compound 13c17 was also synthesized
and its IC50 value was determined to ensure the tests results are
comparable with published values. Compound 26a has methyl
group instead of the –H group at the R3 position compound 13c;
this led to the 9.2-fold increased potency of the IC50 value from
14.0 nM for 13c to 1.52 nM for 26a. The pyridine-3-yl group at
R4 position of 26a was replaced by a 2-fluoro-pyrindin-5-yl
group to give 26b; the chlorine-substituted analogue 26e was also
PDE4A/B with > 1000-fold selectivity for PDE10A vs.
PDE3A/B and PDE4A/B, as shown in Table 3.
Overall, fifteen cinnoline and six benzimidazole analogues
were synthesized and screened for their in vitro activity as
PDE10A inhibitors. Nine of the twenty-one compounds showed
high in vitro potency for PDE10A with IC50 values ranging from
1.52 to 18.6 nM. The three most potent compounds 26a, 26b, and
33c have IC50 values of 1.52 0.18, 2.86 0.10, and 3.73 0.60
nM, respectively; in addition, these three compounds have >
1000-fold selectivity for PDE10A over PDE3A/B and PDE4A/B
and are structurally suitable compounds for labeling with PET

radionuclides. Further studies will be needed to characterize the
pharmacological behavior of the PET ligands in vivo and
determine their potential as PET tracers for assessing PDE10A in
living subjects.
S. A.; Nelson, F. R.; Proulx-LaFrance, C.; Majchrzak, M. J.;
Ramirez, A. D.; Schmidt, K.; Seymour, P. A.; Siuciak, J. A.;
Tingley, F. D., 3rd; Williams, R. D.; Verhoest, P. R.; Menniti, F.
S. J. Pharm. Exp. Ther. 2008, 325, 681.
8. Tu, Z.; Xu, J. B.; Jones, L. A.; Li, S. H.; Mach, R. H. Nucl. Med.
Biol. 2010, 37, 509.
9. Tu, Z.; Fan, J. D.; Li, S. H.; Jones, L. A.; Cui, J. Q.; Padakanti, P.
K.; Xu, J. B.; Zeng, D. X.; Shoghi, K. I.; Perlmutter, J. S.; Mach,
R. H. Bioorg. Med. Chem. 2011, 19, 1666.
Acknowledgments
This study was supported by the National Institute of Mental
Health (NIMH) and the National Institute of Neurological
Disorders (NINDS) under MH092797, NS061025 and
NS075527, and through funding from the Mallinckrodt Institute
of Radiology (MIR) at the Washington University School of
Medicine. The authors would also like to thank Lynne Jones for
assistance in preparing the manuscript.
10. Plisson, C.; Salinas, C.; Weinzimmer, D.; Labaree, D.; Lin, S. F.;
Ding, Y. S.; Jakobsen, S.; Smith, P. W.; Eiji, K.; Carson, R. E.;
Gunn, R. N.; Rabiner, E. A. Nucl. Med. Biol. 2011, 38, 875.
11. Celen, S.; Koole, M.; De Angelis, M.; Sannen, I.; Chitneni, S. K.;
Alcazar, J.; Dedeurwaerdere, S.; Moechars, D.; Schmidt, M.;
Verbruggen, A.; Langlois, X.; Van Laere, K.; Andres, J. I.;
Bormans, G. J. Nucl. Med. 2010, 51, 1584.
12. Van Laere, K.; Ahmad, R. U.; Hudyana, H.; Celen, S.; Dubois, K.;
Schmidt, M. E.; Bormans, G.; Koole, M. Eur. J. Nucl. Med. Mol.
Imaging 2013, 40, 254.
Supplementary Data
13. Van Laere, K.; Ahmad, R. U.; Hudyana, H.; Dubois, K.; Schmidt,
M. E.; Celen, S.; Bormans, G.; Koole, M. J. Nucl. Med. 2013, 54,
Supplementary material associated with this article including
the detailed chemical synthesis, yields, NMR data and the in vitro
assay methods are provided in the supporting online information.
1285.
14. Ahmad, R., Bourgeois, S., Postnov, A., Schmidt, M.E., Bormans,
G., Van Laere, K., Vandenberghe, W., Neurology, 2014, 82, 279.
15. Hu, E., Kunz, R.K., Rumfelt, S., Chen, N., Bürli, R., Li, C.,
Andrews, K.L., Zhang, J., Chmait, S., Kogan, J., Lindstrom, M.,
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K.; Florio, V. A. Gene 1999, 234, 109.
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2013, 4, 443.2.
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Drug Discovery Dev. 2009, 12, 458.
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U.S.A. 1999, 96, 7071.
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Christoffersen, C. T.; Nielsen, J.; Kehler, J. Bioorg. Med. Chem.
2011, 19, 642.
4. Hebb, A. L.; Robertson, H. A.; Denovan-Wright, E. M.
Neuroscience 2004, 123, 967.
5. Menniti, F. S.; Chappie, T. A.; Humphrey, J. M.; Schmidt, C. J.
Curr. Opin. Invest. Dr. 2007, 8, 54.
19. Mager, G.; Klocke, R. K.; Kux, A.; Hopp, H. W.; Hilger, H. H.
Am. Heart. J., 1991, 121, 1974.
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S.; Fusco, F. R. PlOS ONE 2010, 5, e13417.
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Fail. Rev. 2009, 14, 255.
7. Schmidt, C. J.; Chapin, D. S.; Cianfrogna, J.; Corman, M. L.;
Hajos, M.; Harms, J. F.; Hoffman, W. E.; Lebel, L. A.; McCarthy,
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BnO
BnO
NO2
CH3
BnO
NH2
CH3
a
c
b
d
CH3
H3CO
H3CO
H3CO
O
O
O
4
6
3
RO
N
RO
H3CO
N
RO
NH2
CH3
N
N
H3CO
H3CO
Cl
OH
O
9: R = CH3
10: R = Bn
7: R = CH3
8: R = Bn
5: R = CH3
6: R = Bn
R1
N
N
H3CO
N
13a: R1 = OCH3
13b: R1= OBn
14a: R1 = OH
N
RO
N
H3C OH
N
H3CO
R1
N
N
e
f
N
H3CO
13c: R1 = OCH3
13d: R1 = OBn
14b: R1 = OH
F
N
N
11: R = OCH3
12: R = Bn
OH
N
Scheme 1. Synthesis of cinnoline analogues
Reagents and conditions:
(a) HNO3, SnCl4, CH2Cl2, -70°C; (b) Fe, NH4HCO3, toluene, water, reflux; (c) NaNO2, acetic acid, 70%H2SO4, Et3N;
(d) POCl3, PCl5; (e) 2-fluoropyridine-5-boronic acid, Pd(PPh3)4, Cs2CO3, diglyme; (f) i. 4-(pyridin-3-yl)piperidin-4-ol or
4-methylpiperidin-4-ol, K2CO3, DMSO, reflux; or ii. K2CO3, DMSO, reflux, then H2, 10% Pd/C, methanol, 75 psi.

BnO
N
O
N
F
N
N
O
N
a,b
N
N
or
H3CO
H3CO
H3CO
Cl
Cl
Cl
10
15
16
H3CO
H3CO
N
N
N
N
CH3
26a
OH
N
R1
R2
N
N
R1
R2
N
F
N
N
: R1 = R2 = OCH3,
R1
R2
N
26b
N
26c: R1-R2= OCH2O,
f
c
: R1 = R2 = H
N
26d
CH3
N
Cl
CH3
26b-d
26f
26h-i
1
R2 = OCH3
26f
: R
=
=
O
O
OH
19-24
9-10
15-18
1
R2 = OCH3
26h
: R
N
N
1
2
F
17
18
: R -R = OCH2O
: R1 = R2 = H
1
R2 = OCH3
O
F
26i
: R
=
H3CO
H3CO
N
N
N
N
CH3
26e
OH
N
Cl
H3CO
H3CO
N
N
N
Cl
OH
OH
N
d, e
g
N
B
N
Cl
HO
N
HO
NH
N
25
OH
N
26g
Scheme 2. Synthesis of cinnoline derivatives with substitution in the pyridine ring
Reagents and conditions:
(a) H2 (75 psi), 10% Pd/C, MeOH; (b) 2-(bromomethyl)quinoline or 1-bromo-3-fluoropropane, NaH, THF.(c) 2-fluoro-3-methylpyridine-5-boronic
acid, Pd(PPh3)4, Cs2CO3, 1,2-dimethoxyethane; (d) 5-bromo-2,3-dichloro-pyridin, K2CO3, DMSO, 110 °C; (e) bis(pinacolato)diboron, KOAc,
(1,1'-bis(diphenylphosphino)ferrocene)Pd(II) dichloride, dioxane, 120 °C; (f) piperidinol, K2CO3, DMSO, 100 °C; (g) 9, Pd(PPh3)4, Cs2CO3, 1,2-
dimethoxyethane.

H
N
O
O
N
N
O
N
a
b
c
N
N
N
Me
Me
N
H
OMe
OH
OMe
O
27
28
29
30
N
N
Me
d
N
O
Br
31
f
e
O
O
N
N
N
N
Me
Me
N
N
O
O
R1
Me3Sn
33a-c
32
g
O
N
N
33a: R1
33b: R1
33c: R1
=
=
=
Me
N
O
R1
32d-f
OMe
O
O
O
N
33d: R1=
33e: R1=
33f: R1=
N
OMe
O
Scheme 3. Syntheses of new benzimidazole analogues
Reagents and conditions:
(a) 4-Methoxybenzoyl chloride, pyridine, Et3N, NaOH, reflux; (b) CH3I, NaH, DMF; (c) BBr3, DCM; (d) 3-bromo-2-chloropyridine, K2CO3,
Cs2CO3, DMSO; (e) boronic acid ester, K2CO3, Pd(PPh3)4; (f) hexamethyltin, K2CO3, Pd(PPh3)4, toluene; (g) substituted acyl chloride or
aromatic or heteroaromatic boronic acid, palladium.

Table 1: The PDE10A inhibition activity (IC50 nM) of cinnoline analogues
Compound#
13a
R1
R2
-OCH3
R3
R4
IC50 (nM)a
18.4 6.0
4,250 520
14.0 2.0
1,550 260
10,800 1,500
6,620 600
1.52 0.18
2.86 0.10
NAb
-OCH3
-H
CH3
13b
-OBn
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-H
CH3
13c
-OCH3
-H
pyridin-3-yl
13d
-OBn
-H
pyridin-3-yl
14a
-OH
-H
CH3
14b
-OH
-H
pyridine-3-yl
pyridine-3-yl
2-fluoro-pyridin-5-yl
2-fluoro-pyridin-5-yl
2-fluoro-pyridin-5-yl
2-chloro-pyridin-5-yl
2-fluoro-pyridin-5-yl
pyridin-3-yl
26a
-OCH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-Cl
26b
-OCH3
26c
-O-CH2-O-
26d
-H
-H
NAb
26e
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
9.8 1.3
26f
-OBn
350 23
26g
-OCH3
5.52 0.33
518 86
26h
2-(oxymethyl)-quinolinyl
fluoropropoxy
-CH3
-CH3
2-fluoro-pyridin-5-yl
2-fluoro-pyridin-5-yl
26i
79.3 3.6
a IC50 value (mean SD nM) were determined in at least three experiments; b NA = no inhibition activity

Table 2: The PDE10A inhibition activity (IC50 nM) of benzimidazole analogues
Compound #
R1
IC50 (nM)a
18.6 5.3
8.00 1.38
3.73 0.60
NAa
33a
33b
33c
33d
33e
33f
phenyl
4-methoxyphenyl
pyridine-3-yl
benzoyl
4-methoxybenzoyl
N-acetylpiperidin-4-ethanoyl
NAa
>1.9×103
a IC50 value (mean SD nM) were determined in at least three experiments;
b NA = no inhibition activity.

Table 3. The inhibition activity (IC50 nM) of compounds 26a, 26b, and 33c towards PDE 3A&B, PDE4A & B*a
Compound #
PDE10A (nM)
1.52 0.18
2.86 0.10
3.73 0.60
PDE3A (nM)
3,070 180
PDE3B (nM)
4,110 360
PDE4A (nM)
7,830 800
PDE4B (nM)
8,730 730
26a
26b
33c
3,700 250
6,540 520
25,400 3,600
403,00 6,700
30,600 400
25,900 2,900
167,000 52,000
234,000 66,000
a IC50 value (mean SD nM) were determined in at least three experiments