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Background: Phosphodiesterase 7 (PDE7) is a high affinity cAMP-specific PDE whose functional role in T cells has been the subject of some controversy. Recent findings on tissue distribution, however, support the hypothesis that PDE7 could be a good target for the treatment of airway diseases, T-cell related diseases or even CNS disorders. Objective/method: This review discloses recent discoveries of selective PDE7 and PDE4/PDE7 dual inhibitors with special emphasis on their potential for neurological and inflammatory diseases. Conclusion: PDE7 inhibitors constitute a new approach to be explored for the treatment of neurodegenerative disorders.
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10.1517/13543770802364840 © 2008 Informa UK Ltd ISSN 1354-3776 1127
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PDE7 inhibitors as new
drugs for neurological and
infl ammatory disorders
Carmen Gil , Nuria E Campillo , Daniel I Perez & Ana Martinez
Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
Background : Phosphodiesterase 7 (PDE7) is a high affinity cAMP-specific PDE
whose functional role in T cells has been the subject of some controversy.
Recent findings on tissue distribution, however, support the hypothesis that
PDE7 could be a good target for the treatment of airway diseases, T-cell
related diseases or even CNS disorders. Objective/method : This review
discloses recent discoveries of selective PDE7 and PDE4/PDE7 dual inhibitors
with special emphasis on their potential for neurological and inflammatory
diseases. Conclusion : PDE7 inhibitors constitute a new approach to be
explored for the treatment of neurodegenerative disorders.
Keywords: dual PDE7/PDE4 inhibitors , inflammatory diseases , neurological diseases ,
PDE7 inhibitors
Expert Opin. Ther. Patents (2008) 18(10):1127-1139
1. Introduction
Phosphodiesterases (PDEs) selectively degrade cyclic purine nucleotides (cAMP and
cGMP) that serve as second messengers in a number of cellular pathways. PDEs
have proven to be drug-able targets, with compounds on the market or in late-stage
clinical develop ment for a variety of diseases [1] . Theophylline ( 1 ) was probably the
first non-selective PDE inhibitor to be used clinically for the treatment of asthma,
for which it acts as bronchodilator [2] . However, the known PDEs heterogeneity
led to the synthesis of highly selective inhibitors [3] , which have demonstrated
efficacy in a variety of disorders such as cilostazol ( 2 ) (PDE3) for intermittent
claudication [4] , cilomilast ( 3 ) (PDE4) for chronic inflammation [5] , and sildenafil ( 4 )
(PDE5) for male erectile dysfunction and pulmonary hypertension ( Figure 1 ) [6] .
Recently, several reports suggest that PDEs are new targets for CNS diseases [7] .
Virtually all PDEs are expressed in the CNS, making this gene family particularly
attractive as source of new targets for the treatment of psychiatric and
neurodegenerative disorders. Moreover, PDEs inhibitors emerge as promising
new drugs for the treatment of dementia, cognitive disorders, depression
and/or schizophrenia [8-10] .
In this way, cilostazol ( 2 ), a selective PDE3 inhibitor, has been shown to
reduce neuronal cell death after a transient cerebral infarction [11] and also
promote survival of axotomized retinal ganglion [12] . Sildenafil ( 4 ) may improve
learning by modulating NO–cGMP signal transduction, a pathway implicated in
age-related cognitive decline and neurodegenerative diseases [13] . Selective PDE10A
inhibitors are potent antipsychotic agents with potential to improve some of the
cognitive symptoms of schizophrenia [14] and PDE4 inhibitors represent a novel
approach for the treatment of memory deficits [15] . Memory Pharmaceuticals has
one PDE4 inhibitor, namely MEM 1414, which chemical structure is not yet
disclosed, in clinical development for Alzheimer’s disease. MEM 1414 has demonstrated
efficacy in a broad range of preclinical cognition and anti-inflammatory models.
1. Introduction
2. PDE7 inhibitors
3. Dual PDE7/PDE4 inhibitors
4. Expert opinion
PDE7 inhibitors as new drugs for neurological and infl ammatory disorders
1128 Expert Opin. Ther. Patents (2008) 18(10)
In addition, Phase I studies have demonstrated a favorable
safety profile for the compound overall and particularly with
respect to nausea and vomiting, which has limited the
development of other PDE4 compounds [16] . Furthermore,
it has been demonstrated that PDE8B increases in cortical
and hippocampal areas of brains from advanced Alzheimer’s
patients [17] .
Among the 11 PDEs isoenzymes identified so far, PDE7
is a cAMP-specific enzyme insensitive to rolipram (PDE4
inhibitor), expressed across a variety of brain structures apart
from its expression on T cells
[18] . PDE7 emerged as a new
therapeutic target not only for a variety of immunological
and immunodeficiency conditions to alleviate chronic
inflammation [19] but also for several neurodegenerative
disorders including multiple sclerosis in which both
autoimmune system and CNS are implicated [20] .
Two genes (PDE7A, PDE7B) have been identified in
mice, rats and humans that encode PDE7 isoenzymes
sharing > 70% of sequence homology. Distribution of both
isoenzymes is not equal and it is believed to have tissue-
specific functions. Thus, whereas PDE7A is abundantly
expressed in the lungs and hematopoietic cells among
others [21] , high levels of PDE7B are detected in pancreas,
heart, thyroid and skeletal muscles [22] . However, PDE7A
and PDE7B mRNA are also colocalized in some tissues such
as osteoblasts and particular regions of the brain that include
several cortical areas, the dentate gyrus, most components of
the olfactory system, the striatum, many thalamic nuclei
and pyramidal cells of hippocampus [23,24] .
Although the functions of PDE7A and PDE7B in central
and peripheral tissues are not completely proved today
[25] ,
the discovery and use of selective PDE7 inhibitors have
shown important biological functions [18,26] opening the
possibility of a new era of effective drugs [27] . Recently, the
interest in this area is growing, being available assays for
screening of PDE7 selective inhibitors [28] together
crystallographic data of the catalytic site and different
complexes as an important clue for rational design of this
new class of drugs [29] .
The first PDE7 selective inhibitors described at the
beginning of the 21st century were two series of lead
compounds (benzo- and benzothienothiadiazine dioxides
derivatives) that inhibited recombinant human PDE7A
expressed in yeast (
Figure 2 ) [30] . Since that date, several
compounds have emerged [31] as PDE7 inhibitors for in vitro
studies and with a favorable ADME profile for in vivo
studies but none of them have been reported to discriminate
between PDE7A and PDE7B.
The steroid-like structure IC242 [32] from ICOS is a
specific inhibitor of PDE7A with an IC
50 value of 0.37 µM.
This molecule, whose structure has not been disclosed, shows
good selectivity (> 200-fold) for PDE7A over all other PDEs
tested. Discovery of BRL 50481, a selective and potent
PDE7 inhibitor with an IC
50 value on human recombinant
PDE7A of 26 nM, confirmed the anti-inflammatory potential
of these inhibitors and what is more important, it was used
as a pharmacological tool to discover the synergy with PDE4
inhibitors as rolipram in the cAMP modulation [33] .
N
NN
H
N
O
O
1 Theophylline
N
H
O
O
NN
N
N
2 Cilostazol
3 Cilomilast
N
N
S
OEt
OO
N
HN
N
N
Pr
O
4 Sildenafil
O
MeO
NC
CO2H
Me
Me
Me
Me
Figure 1 . PDE inhibitors on the market.
Gil, Campillo, Perez & Martinez
Expert Opin. Ther. Patents (2008) 18(10) 1129
These data open a new horizon for drug discovery: it is
not only relevant to discover selective PDE7 inhibitors as
potential neurological drugs but also PDE4/PDE7 dual
inhibitors emerge as a promising strategy to overcome
adverse secondary events found in the development of
PDE4 inhibitors [34] . Moreover, recently these kind of new
potential drugs have been published and their efficacy in a
collagen-induced arthritis model in mice demonstrated [35] .
This article reviews data from the past years regarding
the discovery, design, synthesis and evaluation of
selective PDE7 and PDE4/PDE7 dual inhibitors with
special emphasis in their potential for neurological and
anti-inflammatory diseases.
2. PDE7 inhibitors
2.1 Purine and pyrimidine derivatives
Purine based compounds have demonstrated a great
potential as PDE7 inhibitors ( Figure 3 ). Pitts et al. [36]
reported the identification of a potent purine based
inhibitor of PDE7 ( 8 ) (IC 50 = 0.150 µM) by screening the
Bristol-Myers Squibb compound collection. Variation around
the purine core at C-6 demonstrated that the potency and
PDE selectivity could be improved over the initial lead by
the introduction of an aryl sulfonamide in the structure ( 9 ).
But not only improvements in PDE7 potency and selectivity
were studied, physicochemical data also were taken into
account by means of their PAMPA (parallel artificial
membrane permeation assay) and solubility data to develop
a series of fused pyrimidine based inhibitors to allow the
in vivo evaluation. In fact, promising plasma exposures were
seen for compound ( 10 ) when it was administered orally
to mice [37] .
The screening of internal and external databases
from Celltech R&D led to an original guanine lead ( 11 )
with activity against PDE7 and also selectivity over
both PDE4 and PDE3. The synthesis of new guanine
derivatives with enhanced activity was also reported in
2001. Structure–activity relationships studies showed that
8-bromo-guanine ( 12 ) was preferred and a range of
substituents was tolerated in terms of activity in the
aromatic ring of tetrahydronaphtalene [38] .
Furthermore, diverse families of purine related inhibitors
of PDE7 were claimed by Darwin Discovery Limited ( I ) [39]
and Bristol-Myers Squibb ( II – III ) [40,41] for the treatment
of various T-cell mediated diseases including multiple
sclerosis among others. Besides, pyrimidine compounds ( IV ) [42]
and fused pyrimidines as V [43-45] were claimed as PDE7
inhibitors. Pyrazolopyrimidinone derivatives ( VI – VII ) from
Ausbio Pharma [43] have shown not only a potent PDE7
inhibiting action but also the IC
50 values of the compounds
against PDE4 were 10 times or more as weak as the
inhibitory activities of the same compounds against
PDE7 ( Figure 4 ).
2.2 Benzene sulfonamides
The benzene sulfonamide group has proved its influence on
the PDE7 activity in some of the purine inhibitors described
by Bristol-Myers Squibb as derivative ( 9 ) ( Figure 3 ). Celltech
described m -substituted phenyl- N -phenylsulfonamides as PDE7
inhibitors in two applications. One of them claimed both
benzimidazolyl and benzoxazolyl substituted compounds,
5 R = OMe PDE7 IC50 11 μM
PDE3 IC50 27 μM
PDE4 IC50 30 μM
6 R = Ph PDE7 IC50 25 μM
PDE3 IC50 15% @ 20 μM
PDE4 IC50 2% @ 20 μM
NH
SO2
N
S
O
O
R
7 PDE7 IC50 8 μM
PDE3 IC50 24 μM
PDE4 IC50 19 μM
NH
SO2
N
O
Cl
Cl
Figure 2 . Some examples of the fi rst PDE7 inhibitors.
PDE7 inhibitors as new drugs for neurological and infl ammatory disorders
1130 Expert Opin. Ther. Patents (2008) 18(10)
such as ( 13 ) and ( 14 ) [46] , whereas the other claimed acyclic
aryl substituted derivatives, such as ( 15 ) ( Figure 5 ) [47] .
SmithKline Beecham developed also a benzene sulfonamide
series [48] as PDE7 inhibitors that may be useful in the
treatment of autoimmune disease.
In 2002 BYK Gulden Lomberg Chemische Fabrik
GMBH reported two of the most active compounds as two
series of 3,4-dihydroisoquinolines bearing a sulfonamide
group ( 16 – 17 ) [49,50] .
The first fully documented PDE7 inhibitor with acceptable
selectivity for in vitro studies was published in 2004. This
compound, 3-( N,N -dimethylsulfonamido)-4-methyl-nitrobenzene,
called BRL 50481 ( 18 ) [33] , is a benzene sulfonamide derivative
with nanomolar potency as PDE7 inhibitor. BRL 50481
was poorly active in suppressing human T-cell proliferation
and TNF- α release from monocytes and macrophages
but, nevertheless, acted in at least an additive manner with
the PDE4 inhibitor rolipram. These findings suggest that
hybrid PDE4/PDE7 inhibitors may be more efficient and
display a superior therapeutic index than a PDE4 inhibitor
alone. This is an important consideration as the two most
clinically advanced PDE4 inhibitors in trials of COPD
(chronic obstructive pulmonary disease) are compromised by
dose-limiting side effects. In this respect, it is noteworthy
N
NN
N
N
H
HN
Et
N
S
EtO2C
OMe
OMe
N
NN
N
N
H
HN
Et
N
S
EtO2C
SO2NH2
PDE7 IC50 0.010 μM
PDE1 IC50 0.95 μM
PDE2 IC50 0.95 μM
PDE3 IC50 2.97 μM
PDE4 IC50 0.55 μM
PDE5 IC50 0.011 μM
N
NN
N
H
N
N
H
N
S
EtO2C
OMe
OMe
OMe
PDE7 IC50 0.006 μM
HN
NN
N
Br
O
H2N
R
11 R = H PDE7 IC50 4.88 μM
PDE3 IC50 30% @ 10 μM
PDE4 IC50 15% @ 10 μM
12 R = 2-Br PDE7 IC50 1.31 μM
PDE3 IC50 14% @ 10 μM
PDE4 IC50 10% @ 10 μM
PDE7 IC50 0.150 μM
PDE1 IC50 0.22 μM
PDE2 IC50 1.7 μM
PDE3 IC50 0.58 μM
PDE4 IC50 1.1 μM
PDE5 IC50 0.27 μM
89
10
Me
Me
Me
Figure 3 . Purine and pyrimidine derivative inhibitors of PDE7.
Gil, Campillo, Perez & Martinez
Expert Opin. Ther. Patents (2008) 18(10) 1131
that several pharmaceutical companies have filed patents
claiming for dual PDE4/PDE7 inhibitors with potential
anti-inflammatory activity, as is commented in Section 3.
BRL 50481 is used today as the reference standard to
explore PDE7 signaling in cells. Treatment of osteoblast
differentiated from human mesenchymal stem cells with the
selective PDE7 inhibitor BRL 50481 increases mineralization
up to threefold compared to control experiments [51] . These
results point out an important role of PDE7 in the regulation
of osteoblastic differentiation and open new pathways for
further therapeutic applications of PDE7 inhibitors.
2.3 Spiroquinazolines
Until now only three articles [52-54] and eight patents have
been published about this new family of spiroquinazolines
derivatives as PDE7 inhibitors. In fact, Pfizer is the unique
company that has shown the PDE7 inhibitory activity of
this kind of heterocycles.
Lorthiois et al. identified by high-throughput screening
the spiroquinazolinone ( 19 ), which inhibited PDE7 with
an IC
50 of 0.17 µM [53] . Optimization of this key lead
compound was performed searching for structures of a potent
PDE7 inhibitor, with an IC
50 range of 0.07 – 0.014 µM.
Some of the best compounds also showed certain selectivity
versus PDE7A1, 3A, 4D and 5. Based on these results,
Bernardelli et al. [54] performed different structural
modification to improve the balance between potency,
selectivity (versus other PDEs) and solubility (improving
drug-like properties) [55] .
The different families of derivatives ( 19 27 ) ( Table 1 )
together with the methodology used to prepare these
compounds, the inhibitory activity and the use in the
treatment of different disorders such as T-cell-related and
autoimmune diseases are claimed by Pfizer and Warner-Lambert
(now part of Pfizer) [56-59] . These compounds showed
IC
50 values comprised between 0.004 and 19 µM. Structure–
activity relationship studies highlighted the importance of
chlorine atom at the position 8 to retain biological activity.
On the other hand the best biological results were
observed when the position 6 was substituted by aryl or
heteroaryl groups. Pfizer also reported the use of these
compounds in the treatment of neuropathic pain in
human/animal body [60] .
2.4 Azo compounds
In 2001 Merck published five applications of imidazole,
isoxazole, pyrrole and imidazopyridine derivatives ( VIII – XII )
used as PDE7 inhibitors with application for the treatment
of immune disorders (e.g., multiple sclerosis) ( Figure 6 ) [61-65] .
More interesting is the 1,3,4 thiadiazole ( 28 ) ( Figure 7 )
identified by Vergne et al. [66] as a weak PDE7 inhibitor
with an IC
50 of 1.5 µM from high-throughput screening.
The optimization of this lead compound led to obtain a
structurally novel series of PDE7 inhibitors ( 28 – 33 ) ( Figure 7 )
displaying nanomolar inhibitory activity and exhibiting high
selectivity over PDE4. Some of the best compounds, as
thiadiazoles amide subseries, showed in rats low bioavailabilities
(< 20%) and high clearances (> 100 ml/min).
Based on these results, the identification of the major
in vivo metabolites of compound 33 after oral (p.o.) and
intravenous (i.v.) rat administration was performed, to
remove or alter the functionalities associated with the rapid
NZ
Y
X
R1
R2
O
R3J2
N
J1
R5
N
N
N
Z
R2
R1
N
N
J
N
N
N
Z
R2
R1
Y
L
J
N
N
N
Z
R2
R1
I II III IV
HN
N
N
N
O
R2
R1
A
B
R3
N
N
N
L
R2
R1
Y2
Y1
Y3
VVI
N
HN
N
N
O
R2
R1
A
B
R3
VII
Figure 4 . Purine and pyrimidine related inhibitors of PDE7.
PDE7 inhibitors as new drugs for neurological and infl ammatory disorders
1132 Expert Opin. Ther. Patents (2008) 18(10)
13
SN
H
Cl
NNH
OO
NO2
14
SN
H
NO
OO
Cl
HO
O
15
SN
H
OO
O
O
O
N
H
NO2
N
NH
S
R
OMe
Cl
O
O
16 R = Me PDE7 IC50 0.120 μM
17 R = OCF3 PDE7 IC50 0.032 μM
PDE7 IC50 0.026 μM
PDE1B IC50 > 100 μM
PDE1C IC50 > 100 μM
PDE2 IC50 > 100 μM
PDE4 IC50 62 μM
PDE5 IC50 > 100 μM
SN
OO
NO2
18 BRL 50481
Me
Me
Me
Me
Figure 5 . PDE7 inhibitors with benzene sulfonamide moiety.
rate of metabolism. Two principal sites of metabolism
were found such as the oxidation of the cyclohexyl ring
(hepatic clearance) and the hydrolysis of the amide group
(extra-hepatic clearance) [67] . The authors proposed that
the hydrolysis of the amide group (extra-hepatic route)
was responsible for the higher rat in vivo clearance. To
improve these pharmacokinetic parameters without loss of
inhibitory activity different structures were generated finding
some interesting compounds with good PDE inhibitory
profile ( Table 2 ).
Jones et al. [68] investigated the performance of compound ( 36 ),
also called PF 0332040, as selective inhibitor of PDE7 in
inflammatory cells in vitro , discovering that this compound
only exhibits an inhibitory effect on human peripheral blood
mixed mononuclear cells.
All of these thiadiazoles [69] together with a new family
of thiadiazol amines, sharing the same scaffold depicted
in Table 2 [70] , were described by Warner-Lambert as
PDE7 inhibitors.
New 4-aminothieno[2,3- d ]pyrimidine-6-carbonitrile derivatives
were claimed by Almirall Prodesfarma as potent and selective
inhibitors of PDE7, which can be used for the treatment of
diseases susceptible to amelioration by inhibition of PDE7
such as multiple sclerosis [71] . All the examples reported
in the application have an IC
50 between 1 and 10 µM.
Compounds that showed a particular good selectivity were
those with a phenyl or benzyl group in the pyrimide ring
as ( XIII ) and ( XIV ) ( Figure 8 ).
3. Dual PDE7/PDE4 inhibitors
As mentioned before, the development of dual PDE7/PDE4
inhibitors could avoid side effects (nausea, emesis) of
PDE4 inhibitors and could also regulate pro-inflammatory
Gil, Campillo, Perez & Martinez
Expert Opin. Ther. Patents (2008) 18(10) 1133
Table 1 . In vitro potency (IC
50 , µM) and selectivity for spiro compounds (19 – 27).
N
H
NH
O
5
7
Cl
6
R
Compound R PDE7A1 * PDE1
PDE3A3 * PDE4D3 * PDE5
§
19 0.170
20 5-Cl 0.014
21 6-Phenyl 0.016 3.26 > 101 1.42 69.8
22 6- p -C
6 H
4 -CO
2 H 0.013 0.89 21.3 0.47 8.50
23 6- m -C
6 H
4 -CONH-(CH
2 )
3 -NMe
2 0.019 5.16 78.1 1.46 > 84.9
24 6- p -C
6 H
4 -CO-N-Methylpiperazine 0.014 7.01 29.3 1.70 29.3
25 5-O-CH
2 -(5-CO
2 Et-Furan2-yl) 0.011 2.98 78 1.02 80
26 5-CH
2 -(1H-Tetrazol-5-yl) 0.004 0.32
11.8 0.328 > 88
27 5-O-CH
2 CH
2 NHCH
2 CO
2 H 0.042 29.7 > 101 14.7 > 101
* Measured against the human full-length enzyme produced in baculovirus infected sf9 cells.
Measured against the human partially purifi ed from THP-1 cell pellets.
§ Measured against the human partially purifi ed from MCF-7 cell pellets.
Measured against the human full-length PDE1A enzyme produced in baculovirus infected sf9 cells.
VIII IX X
X
N
N
R1
R2
O
NO
H
N
R1
R3
R2
N
NC R3
R2
O
OR4
R1
XI XII
N
N
N
S
X
R1
R2
R3
N
X
N
N
R2
R1
Figure 6 . Azole compounds claimed by Merck.
PDE7 inhibitors as new drugs for neurological and infl ammatory disorders
1134 Expert Opin. Ther. Patents (2008) 18(10)
Table 2 . In vitro and in vivo pharmacokinetic studies.
SN
R2R6
N
N
Me
Compound R
6 R
2 PDE7A1 IC
50 , µM * PDE4D3 IC
50 , µM * Reduction in Cl versus 34 (%)
34 H 4-CONH
2 0.061 15.30 0
35 3-OH- trans 4-CONH
2 0.19 71.64 67
36 3-OH (R,R) 4-CONH
2 0.088 61.62 ND
37 H 4-NHCOMe 0.068 34.25 58
38 2-OH (R,R) 4-SO
2 Me 0.052 20.0 91
* Measured against the human full-length enzyme produced in baculovirus infected sf9 cells.
ND: Not determined.
PDE7A1 IC50 1.500 μM
PDE4D3 IC50 57.00 μM
PDE7A1 IC50 0.140 μM
PDE4D3 IC50 21.33 μM
PDE7A1 IC50 0.140 μM
PDE4D3 IC50 92.33 μM
PDE7A1 IC50 0.061 μM
PDE4D3 IC50 15.30 μM
N
N
SN
NH
O
N
O
Cl
N
N
SN
N
N
SN
N
O
Me2N
N
N
SN
NH2
O
NN
H2N
N
N
SN
Cl
COOH
N
N
SN
28 29
PDE7A1 IC50 0.030 μM
PDE4D3 IC50 8.77 μM
30
PDE7A1 IC50 0.47 μM
PDE4D3 IC50 > 101 μM
31
32 33
Me
Me
Me
Me
Me
Me
Me
Figure 7 . PDE7 inhibitors with a thiadiazole heterocycle in the chemical structure.
Gil, Campillo, Perez & Martinez
Expert Opin. Ther. Patents (2008) 18(10) 1135
XIII XIV
N
N
S
NC
R1R2
R3
N
R3
N
N
S
NC
R1R2
N
Me
Me
Figure 8 . Thieno pyrimidines PDE7 inhibitors.
and T-cell function. Apart from these benefits, these
dual inhibitors might be useful for the treatment of
immune and inflammatory diseases [72] . The potential
role of PDE7 in human T-cell function was determined
using a dual PDE7/PDE4 inhibitor. Thus, the PDE
inhibitor namely T-2585 ( 39 ) [73] , which suppressed PDE4
isoenzyme activity with high potency (IC
50 = 0.1 nM)
and PDE7A with low potency (IC
50 = 1.5 µM), inhibited
cytokine synthesis, proliferation and CD25 expression of
human peripheral blood mononuclear cells in the dose
range at which the drug suppressed PDE7A activity.
Surprisingly these effects were not observed using
the selective and potent PDE4 inhibitor RP 73401
(IC
50 = 0.3 nM) [26] . The following paragraphs will
focus on recent advances on these interesting dual
inhibitors of PDE7/PDE4 ( Figure 9 ).
Compound YM-393059 ( 40 ) from Astellas Pharma,
Inc. is a novel PDE7A and -4 dual inhibitor. The
compound inhibits PDE7A isoenzyme with a potency
of IC
50 = 0.014 µM and PDE4 with IC
50 = 0.630 µM.
This compound inhibited both Th1 (IL-2 and interferon- γ )
and Th2 (IL-4) cytokines in vitro and in vivo .
Another advantage of this compound to be considered
was that it did not induce emesis; so it would be an
attractive candidate for the treatment of a wide variety of
inflammatory disorders, such as asthma, COPD and
rheumatoid arthritis
[74] . YM-393059 had also an inhibitory
effect on ear edema and tended to reduce serum IgE
antibody production in a chronic dermatitis model
proposing this compound for the treatment of allergic
diseases (atopic dermatitis) [75] . Furthermore YM-393059
improved mouse collagen-induced arthritis through the
suppression of pro-inflammatory cytokine (TNF-α and
IL-1 β ) production confirming its use for the treatment
of autoimmune disorders (rheumatoid arthritis) [35] .
Compounds ( 41 ) and ( 42 ) developed by Bristol-Myers
Squibb inhibited PDE7/PDE4 with IC
50 values of 0.030/3.0
and 0.060/3.2 µM, respectively. These purine derivatives
have been proposed as dual inhibitors for the treatment of
leukocyte activation-associated disorders such as multiple
sclerosis, psoriasis, asthma, transplant rejection and chronic
obstructive pulmonary disease [76-78] .
Phtalazinones ( 43 ) and ( 44 ) from Altana Pharma
inhibited PDE7 (0.398 and 0.079) and PDE4 (0.050
and 0.039) in a micromolar concentration, respectively.
Both compounds would be suitable as bronchial
therapeutics and inflammatory disorders. Additionally,
these compounds are of potential value for the treatment
of conditions associated with cerebral metabolic inhibition,
such as cerebral senility, senile dementia (Alzheimer’s disease),
memory impairment associated with Parkinson’s disease or
multi-infarct dementia; also diseases of the CNS, such as
depression or arteriosclerotic dementia. These compounds
according to the literature are distinguished by a low toxicity,
good enteral absorption and the absence of side effects [79] .
Ligand-based virtual screening studies allowed
Castro et al. to identify thiadiazine and quinazoline
derivatives as a new class of PDE7 inhibitors [80] . Based
on these results, new modifications on the quinazoline
scaffold were carried out. In this way, thioxoquinazoline
derivatives ( 45 ) and ( 46 ) inhibited PDE7A1 (IC
50 = 0.1
and 1.0) and PDE4D2 (IC
50 = 1.4 and 5.7) at micro-
molar concentration
[81] . These compounds showed
a synergistic effect with rolipram on the intracellular
cAMP levels.
4. Expert opinion
PDE7 is one of the members of PDE family that has been
identified as being a cAMP-specific PDE. Although it was
first characterized in 1993 and was known for its role
regulating T-cell function, it has attracted little interest until
the beginning of 21st century, in which the first inhibitors
were described in the literature. Further research is needed
but the interest in this new target has increased nowadays
with the potential implication of PDE7 in several important
neurological disorders. Without any doubt, increasing the
levels of cAMP represents a strategy to modulate neuronal
activity. Our hypothesis is based on the fact that an increase
of cAMP level promotes inflammation. Therefore, in diseases
PDE7 inhibitors as new drugs for neurological and infl ammatory disorders
1136 Expert Opin. Ther. Patents (2008) 18(10)
PDE7 IC50 0.398 μM
PDE4 IC50 0.050 μM
PDE7 IC50 0.079 μM
PDE4 IC50 0.039 μM
PDE7 IC50 0.1 μM
PDE4 IC50 1.4 μM
PDE7 IC50 1.0 μM
PDE4 IC50 5.7 μM
N
N
N
O
N
OH
OH
EtO
EtO
(HCl)
PDE7 IC50 1.7 μM
PDE4 IC50 0.00013 μM
N
N
N
S
H
N
N
N
O
O
OMe
N
N
N
N
N
H
OMe
OMe
OMe
S
EtO
O
N
N
N
N
H
N
S
EtO
O
OH
OH
N
N
O
Cl
OMe
N
N
S
S
OH
O
N
N
O
F
OMe
N
N
O
S
F
F
N
N
O
S
F
F
39 T-2585
PDE7 IC50 0.014 μM
PDE4 IC50 0.630 μM
PDE1 IC50 > 10,000 μM
PDE2 IC50 > 10,000 μM
PDE3 IC50 > 10,000 μM
PDE5 IC50 > 10,000 μM
40 YM-393059
PDE7 IC50 0.030 μM
PDE4 IC50 3 μM
41
PDE7 IC50 0.060 μM
PDE4 IC50 3.2 μM
42
43 44 45 46
Me
Me
Me
Me
Me
Me
Me Me Me
Me
Me
Figure 9 . Dual inhibitors of PDE7 and PDE4.
Gil, Campillo, Perez & Martinez
Expert Opin. Ther. Patents (2008) 18(10) 1137
in which an overexpression or an overactivity of PDEs is
produced, inhibitors of PDEs will be useful as therapeutic
agents. This fact has been proved with PDE4 inhibitors for
smooth tissues diseases and COPD, and it would be checked
in the near future with PDE7 inhibitors for neurological
disease, as PDE7 is widely expressed on brain area.
Modulation of the inflammation process is without any
doubt a neuroprotective, well-established strategy.
As predicted before
[82] , this century witnesses the birth of
new and potent PDE7 inhibitors and the publication of several
patent applications, such as the ones reviewed in this manuscript.
It suggests that pharmaceutical companies have active exploratory
research programs to identify PDE7 inhibitors as a new era
of drugs for anti-inflammatory and neurological diseases.
Most probably, the recently described dual PDE7/4
inhibitors could be more effective than a selective PDE4
inhibitor or a selective PDE7 inhibitor in the above
mentioned disease states. It may be owing to an additive or
synergistic inhibition of PDE7 and PDE4 simultaneously.
Development of either selective PDE7 inhibitors or dual
PDE7-PDE4 inhibitor with favorable ADME properties for
in vivo studies will broaden the scope of a novel class of
therapeutics with an innovative mechanism of action
maintaining high levels of intracellular cAMP. These
inhibitors would target a major unmet medical need in a
field in which new and effective therapies are an urgent
social need.
Declaration of interest
The authors state no conflict of interest and have received
no payment in preparation of this manuscript.
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Affi liation
Carmen Gil 1 , Nuria E Campillo 1 ,
Daniel I Perez 2 & Ana Martinez 1
Author for correspondence
1 Instituto de Química Médica (CSIC),
Juan de la Cierva 3,
28006 Madrid, Spain
Tel: +34 91 5622900; Fax: +34 915644853;
E-mail: cgil@iqm.csic.es
2 Delft University of Technology,
Lab. of Biocatalysis and Organic Chemistry,
Julianalaan 136,
2628 BL Delft, The Netherlands
... Inhibition of PDE7 results in elevated cAMP levels leading to decrease in oedema, cellular inflammation, bronchoconstriction as well as release of mucous. Effectiveness of the inhibitors of PDE7 enzyme has been reported recently in animal models as anti-inflammatory agents and denotes as a novel category of drugs for the management of various inflammatory diseases [17][18][19]. BRL50481 (3-(N,Ndimethylsulfonamido)-4-methyl-nitrobenzene) is the only officially available selective inhibitor of PDE7 which was discovered in 2004 [20,21]. ...
... This concept of synergetic effect is supported by the coincidental expression of PDE4 and PDE7 subtypes in various immunity and inflammatory cells [4]. Various dual inhibitors of PDE4 and PDE7 developed include pyrazolo [3,4-b]pyridine derivatives, purine derivatives, pyrimidine derivatives, quinazoline derivatives, isochromenones and isoxazoline spirocyclic scaffold based compounds which had demonstrated their efficacy in a series of in vitro assays as well as animal models and suggest the potential of these compounds for the management of a large range of inflammatory diseases [4,18,[22][23][24][25][26][27][28][29][30]. Development of dual inhibitors of PDE4 and PDE7 will yield novel class of therapeutic agents for treatment of wide-range of inflammatory and immune disorders and have a novel mechanism of action by maintaining high levels of intracellular cAMP. ...
Article
Background: Phosphodiesterase 4 (PDE4) and phosphodiesterase 7 (PDE7), members of PDE superfamily, catalyse hydrolysis of cyclic adenosine monophosphate in pro-inflammatory and immunomodulatory cells leading to increased inflammatory processes. Dual inhibitors of PDE4 and PDE7 are a novel class of drug candidates which can regulate pro-inflammatory as well as immune T-cell function and can be particularly useful in the treatment of a wide variety of immune and inflammatory disorders with less undesirable adverse effects. Objective: The present research work was designed to synthesize and evaluate the anti-inflammatory activity as well as in silico docking studies of some newer substituted 1,3-thiazolidine-2,4-dione derivatives as dual inhibitors of PDE4-PDE7. Method: A new series of substituted 1,3-thiazolidine-2,4-dione derivatives was synthesized and evaluated for anti-inflammatory activity in animal models followed by docking studies to determine the binding interactions for the best fit conformations in the binding site of PDE4 and PDE7 proteins. Results: Amongst the synthesized molecules, compounds 5 and 12 showed higher anti-inflammatory activity in the carrageenan induced rat paw oedema method. The in vivo experimental results were found to be in concordance with that of the in silico results. Conclusion: These molecules can act as the starting hits for the design of safe and effective dual inhibitors of PDE4 and PDE7 for the potential treatment of various inflammatory disorders.
... PDE7A is expressed in high levels in spleen, heart, skeletal muscle and various immune cells and at low levels in the brain while PDE7B is predominantly distributed in striatal brain regions [3,[84][85][86][87][88]. Although only little is known about the (patho-)physiological effects of the enzyme activity, selective PDE7 inhibitors are regarded as potent therapeutics for inflammatory and neurological disorders related with T-cell activation, multiple sclerosis, Parkinson´s disease, Alzheimer´s disease and addiction [89][90][91][92][93][94][95]. ...
... PDE7A is expressed in high levels in spleen, heart, skeletal muscle and various immune cells and at low levels in the brain while PDE7B is predominantly distributed in striatal brain regions [3,[84][85][86][87][88]. Although only little is known about the (patho-)physiological effects of the enzyme activity, selective PDE7 inhibitors are regarded as potent therapeutics for inflammatory and neurological disorders related with T-cell activation, multiple sclerosis, Parkinson's disease, Alzheimer's disease and addiction [89][90][91][92][93][94][95]. ...
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Cyclic nucleotide phosphodiesterases (PDEs) represent one of the key targets in the research field of intracellular signaling related to the second messenger molecules cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). Hence, non-invasive imaging of this enzyme class by positron emission tomography (PET) using appropriate isoform-selective PDE radioligands is gaining importance. This methodology enables the in vivo diagnosis and staging of numerous diseases associated with altered PDE density or activity in the periphery and the central nervous system as well as the translational evaluation of novel PDE inhibitors as therapeutics. In this follow-up review, we summarize the efforts in the development of novel PDE radioligands and highlight (pre-)clinical insights from PET studies using already known PDE radioligands since 2016.
... It is noteworthy that pretreatment of PC12 cells with the combination of rolipram and BRL50481 improved further ROS and MDA levels compared with rolipram or BRL50481 alone. In support of our results, the recently described combined PDE7/4 inhibitors may be more efficacious and display a superior therapeutic index than a selective PDE4 inhibitor or a selective PDE7 inhibitor in the neurodegenerative disorders which are basically related to oxidative stress such as Alzheimer's and Parkinson's disease (Gil et al. 2008;Smith et al. 2004). ...
... It has also been seen that rolipram is due to its anti-inflammatory property has analgesic effect and can be used in treatment and management of chronic pain Kim et al. 2015). On the other hand many studies show the PDE7 inhibitors as a potent and promising antiinflammatory tool and thus PDE7 inhibition can be as a new therapeutic target for inflammatory diseases (Giembycz and Smith 2006;Gil et al. 2008;González-García et al. 2013;Mokry et al. 2013;Nakata et al. 2002;Redondo et al. 2012). ...
Article
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Diabetic neuropathy (DN) is the most common diabetic complication. It is estimated diabetic population will increase to 592 million by the year 2035. This is while at least 50–60% of all diabetic patients will suffer from neuropathy in their lifetime. Oxidative stress, mitochondrial dysfunction, apoptosis, and inflammation are crucial pathways in development and progression of DN. Since there is also no selective and effective therapeutic agent to prevent or treat high glucose (HG)-induced neuronal cell injury, it is crucial to explore tools by which one can reduce factors related to these pathways. Phosphodiesterase 4 and 7 (PDE 4 and 7) regulate oxidative damage, neurodegenaration, and inflammatory responses through modulation of cyclic adenosine monophosphate (cAMP) level, and thus can be as important drug targets for regulating DN. The aim of this study was to evaluate the protective effects of inhibitors of PDE 4 and 7, named rolipram and BRL5048, on HG-induced neurotoxicity in PC12 cells as an in vitro cellular model for DN and determine the possible mechanisms for theirs effects. We report that the PC12 cells pre-treatment with rolipram (2 μM) and/or BRL5048 (0.2 μM) for 60 min and then exposing the cells to HG (4.5 g/L for 72 h) or normal glucose (NG) (1 g/L for 72 h) condition show: (1) significant attenuation in ROS, MDA and TNF-a levels, Bax/Bcl-2 ratio, expression of caspase 3 and UCP2 proteins; (2) significant increase in viability, GSH/GSSG ratio, MMP and ATP levels. All these data together led us to propose PDE 4 and 7 inhibitors, and specifically, rolipram and BRL5048, as potential drugs candidate to be further studied for the prevention and treatment of DN.
... 11,12 Moreover, pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6 are involved in the persistence of pathologic pain by directly activating nociceptive sensory neurons and inflammation-induced central sensitization. 13,14 Thus, phosphodiesterase (PDE)-targeted therapies including PDE4 and PDE7 inhibitors, which increase levels of intracellular cAMP and produce anti-inflammatory effects, have become another option for treating NP. 15,16 The aim of this study was to explore the chromatographic mobilities of a series of 14 amide derivatives of theophylline (Table 1). Among the evaluated amides of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids with multifunctional TRPA1 channel antagonists and PDE4/7 inhibitors and in vivo analgesic activity the compounds with 4-tert-butyl, 4isopropyl, 4-sec-butyl or 2-hydroxy-5-tert-butyl substituent in the phenyl ring were the most active towards both these targets. ...
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Lipophilicity is one of the principal QSAR parameters which influences among others the pharmacodynamics and pharmacokinetic properties of a drug candidates. In this paper, the lipophilicity of 14 amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 channel antagonists and phosphodiesterase 4/7 inhibitors with analgesic activity were investigated, using reversed-phase thin-layer chromatography method. It was observed that the retention behavior of the analyzed compounds was dependent on their structural features i.e. an aliphatic linker length, a kind of substituent at 8 position of purine-2,6-dione scaffold as well as on a substitution in a phenyl group. The experimental parameters (RM0) were compared with computationally calculated partition coefficient values by Principal Component Analysis (PCA). To verify the influence of lipophilic parameter of the investigated compounds on their biological activity the Kruskal-Wallis test was performed. The lowest lipophilicity was observed for the compounds with weak PDE4/7 inhibitory potency. The differences between the lipophilicity of potent inhibitors and inactive compounds were statistically significant. It was found that the presence of more lipophilic propoxy- or butoxy- substituents as well as the elongation of the aliphatic chain to propylene one between the purine-2,6-dione core and amide group were preferable for desired multifunctional activity.
... The inhibition of phosphodiesterase 7 (PDE7) results in elevated Cyclic adenosine monophosphate (cAMP) levels leading to a decrease in edema, cellular inflammation, and bronchoconstriction, as well as the release of mucous. The effectiveness of the inhibitors of PDE7 enzyme has been reported recently in animal models as anti-inflammatory agents and denotes as a novel category of drugs for the management of various inflammatory diseases (Gil et al., 2008;Grewal et al., 2017a). Due to the emerging need of improved analogs, various heterocyclic compounds are synthesized, including pyrazole compounds and their derivatives as PDE7 inhibitors (Redondo et al., 2012). ...
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Schiff bases are biologically diverse molecules with vast pharmacological activities and have been an area of interest in medicinal chemistry. Recently, this class also attributed new targets for drug development and research. The present study reveals the design and synthesis of the novel Schiff bases as prospective anti-inflammatory agents from the combination of 4-aminopyrazone with different aldehydes with a simple and effective grinding technique to produce different yellow-shaded products. The compounds formed were analyzed by IR spectra and 1H-nuclear magnetic resonance. Synthesized derivatives were evaluated in silico using docking studies to predict phosphodiesterase 7 (PDE7) inhibition and to investigate the binding interactions of the synthesized derivatives with active site residues of PDE7. These compounds showed appreciable binding interactions with PDE7 protein and good drug-like properties.
... PDE7 inhibition leads to increased levels of cAMP resulting in decrease in oedema, cellular inflammation, mucous secretion and bronchoconstriction. Efficacy of the inhibitors of PDE7 enzyme has been reported recently in animal models as anti-inflammatory agents and represents a new class of drugs the management of various inflammatory disorders (Gil et al., 2008;Redondo et al., 2012;Grewal et al., 2017a). BRL50481 (3-(N,N-dimethylsulfonamido)-4-methylnitrobenzene) is the only officially available selective inhibitor of PDE7 which was discovered in 2004 (Smith et al., 2004;Christensen et al., 2012). ...
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