Discovery of novel 1,4-dihydropyridine-based PDE4 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.11.121

Substituted 1,4-dihydropyridines were discovered as a novel and potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationships within this series have been carried out and studies revealed that the dihydropyridine core, with indole moiety and 3,4-dimethoxybenzyl group, is a potent analogue for PDE4 inhibition. These novel series of compounds were prepared via a 3-component reaction in a single pot. In vitro biological activity, modeling studies and crystallography data are also reported.

Full text of DOI:10.1016/j.bmcl.2012.11.121

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1104–1109
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of novel 1,4-dihydropyridine-based PDE4 inhibitors
Rajamohan R. Poondra a, , Ratnam V. Nallamelli a, , Chandana Lakshmi Teja Meda b, , B. N. V. Srinivas a,
⇑
Anushka Grover c, Jyotsna Muttabathula c, Sreedhara R. Voleti c, Balasubramanian Sridhar d, Manojit Pal a,
Kishore V. L. Parsa b,
⇑
a Department of Medicinal Chemistry, Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India
b Department of Biology, Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India
c Department of CADD, Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India
d Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted 1,4-dihydropyridines were discovered as a novel and potent series of phosphodiesterase 4
(PDE4) inhibitors. Structure–activity relationships within this series have been carried out and studies
revealed that the dihydropyridine core, with indole moiety and 3,4-dimethoxybenzyl group, is a potent
analogue for PDE4 inhibition. These novel series of compounds were prepared via a 3-component
reaction in a single pot. In vitro biological activity, modeling studies and crystallography data are also
reported.
Received 10 September 2012
Revised 14 November 2012
Accepted 30 November 2012
Available online 8 December 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Dihydropyridine scaffold
PDE4 inhibitors
Docking
X-ray crystallography
Phosphodiesterase 4 (PDE4) is a member of PDE enzyme family
and is responsible for the regulation of intracellular cyclic adeno-
sine monophosphate (cAMP).1 The PDE4s are characterized by
selective, hydrolytic degradation of cyclic AMP and sensitivity to
inhibition by a wide selection of inhibitors. A number of inhibitors
of the PDE4s have been discovered in recent years, and beneficial
pharmacological effects resulting from PDE4 inhibition have been
shown in a variety of disease models.2 Therefore, considerable
interest continues in the discovery of potent and selective
inhibitors of PDE4.
To pursue our investigation on PDE4 inhibiting compounds, we
started with the information that derivatives of nicotinic acid pos-
sess PDE4 inhibiting properties. Recently, nicotinamide derivatives
are claimed as selective inhibitors of PDE4 which may be useful for
the treatment of inflammatory diseases such as asthma, chronic
obstructive pulmonary disease (COPD), adult respiratory distress
syndrome (ARDS), rheumatoid arthritis and psoriasis, as well as
central nervous system (CNS) disorders such as depression.3 Thus,
we decided to explore further on the nicotinamide derivatives and
related structural cores for the design of novel compounds, poten-
tially active inhibitors for PDE4 (Fig. 1).
Nitrogen heterocyclic frameworks are prevalent in pharmaceu-
ticals and biologically functional molecules. 1,4-Dihydropyridines
(1,4-DHPs) are widely known class of biologically active nitrogen
heterocycles as well as analogues of NADH coenzymes. 1,4-DHP
scaffold is one of the most versatile pharmacophores since it has
been found as the central core in many pharmaceuticals.4 The
well-known marketed drugs are the series of 1,4-DHP-based
calcium channel blockers such as cilnidipine, nicardipine, nifedi-
pine, and nimodipine (Fig. 1), which are widely used for the treat-
ment of hypertension and cardiovascular diseases.4,5 1,4-DHPs
have been considered as prototypical calcium channel blockers to
modulate calcium current at the voltage-dependent calcium chan-
nels (VDCCs), and widely used in clinic. Cilnidipine is a potent dual
blocker for N/L-type VDCCs and is currently used for the treatment
of hypertension. Nimodipine and nicardipine are also calcium
channel blockers, and inhibited the cyclic AMP phosphodiesterase
(PDE) activity of purified PDE in a cell-free preparation. 1,4-DHPs
have been reported with miscellaneous new functions in recent
years, including antitumor,6 and anti-diabetic agents,7 HIV prote-
ase inhibitors,8 and drugs in the treatment of a number of other
diseases.9–11 In addition, the results obtained from the study with
1,4-DHPs as inhibition and activation of Sirtuins,12 inhibition of
cytochrome P450,13 ACE inhibition, and blood pressure control
on chronic, non-diabetic nephropathies.14
⇑
Corresponding authors. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail addresses: rajamohanreddyp@ilsresearch.org (R.R. Poondra), kishorep@
ilsresearch.org (K.V.L. Parsa).
Thus, designing and screening compounds, searching for novel
biological activity of 1,4-DHPs is highly desirable work. To the best
of our knowledge, this is the first report of new function of 1,
These authors contribute equally to this work.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.11.121

R. R. Poondra et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1104–1109
1105
FG
NO2
O
O
O
O
O
O
O
OH
R1O
OR2
EtO
OEt
FG
N
H
S
N
N
H
N
N
Nicotinic acid
Previous work
This work
(1,4-DHP drugs for
(PDE4 Inhibitors)
cardiovascular diseases)
F
DHP-based
Nicotinic acid
R1
drugs
R2
N
derivative
O
Cilnidipine
Ph
Ph
Nicardipine
Nifedipine
Methyl
Methyl
Methyl
O
Nimodipine
Isopropyl
Figure 1. Nicotinic acid and dihydropyridine derivatives.
4-DHPs. Here, we examined the potential of the previously unex-
plored dihydropyridine scaffold in developing PDE4 inhibitors;
we have screened our in-house compound collection in search of
novel class of inhibitors. To our surprise, compound 9 displayed
R1
+
O
R1
O
O
O
O
H
AcOH
EtO
OEt
EtO
OEt
80-100°C
15 min - 2 hr
reasonable inhibition of PDE4 (58% inhibition at 30 lM). This result
N
R2
NH2
R2
has prompted our use of 9 as a starting point for improving the
potency for PDE4. We targeted two of the major regions of 9 for
synthetic explorations: (1) the pendant phenyl ring, and (2) the
pyridine nitrogen. Accordingly, we prepared a series of 1,4-DHP
Scheme 1. Synthesis of substituted 1,4-dihydropyridine derivatives.
Table 1
Synthesis of substituted 1,4-dihydropyridine derivatives
Entry
Aldehyde
Amine
Timea/Yieldb
30/75
Entry
Aldehyde
Amine
H2N
O
Timea/Yieldb
30/72
Cl
CHO
CHO
MeO
CHO
OMe
H2N
1
16
O
O2N
OMe
OMe
Cl
Cl
H2N
H2N
2
3
4
30/76
30/77
45/80
17
18
19
15/67
30/84
30/77
CHO
CHO
H2N
H2N
O2N
Cl
Cl
Cl
CHO
CHO
OMe
OMe
CHO
CHO
H2N
Cl
OMe
H2N
H2N
F
Cl
H2N
H2N
OMe
OMe
5
6
30/83
30/84
20
21
30/84
30/73
CHO
F
F
CHO
Cl
Cl
H2N
H2N
CHO
CHO
OMe
OMe
CHO
CHO
OMe
7
8
9
45/87
15/75
15/80
22
23
24
30/73
30/71
OMe
H2N
Cl
Cl
CHO
H2N
H2N
H2N
H2N
Cl
MeO
CHO
MeO
CHO
CF3
15/74
(continued on next page)

1106
R. R. Poondra et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1104–1109
Table 1 (continued)
Entry
Aldehyde
Amine
Cl
Timea/Yieldb
20/79
Entry
Aldehyde
CHO
Amine
Timea/Yieldb
15/64
OMe
OMe
HO
Cl
CHO
10
25
H2N
H2N
H2N
H2N
OMe
OMe
6
MeO
MeO
CHO
CHO
11
30/71
26
30/92
CHO
MeO
CHO
14
H2N
12
13
15/69
15/73
27
28
30/89
15/73
H2N
Cl
CHO
CHO
HO
CHO
CHO
CF3
H2N
H2N
H2N
H2N
HO
MeO
O
O
14
15
30/65
29
30
30/77
30/79
CHO
OMe
OMe
H2N
Cl
CHO
120/53
N
H
H2N
a
Reaction time in minutes.
Isolated yield in %.
b
Table 2
Inhibition of PDE4 with 1,4-DHP derivatives
Compound
R1
R2
% of PDE4B inhibitiona
1
2
3
4
5
6
4-ClC6H4
4-ClC6H4
4-NO2C6H4
4-ClC6H4
3-FC6H4
4-OMeCH2C6H4
4-ClCH2C6H4
4-OMeCH2C6H4
3,4-(OMe)2CH2C6H3
4-OMeCH2C6H4
4-ClCH2C6H4
23
15
38
80
28
8
3-FC6H4
7
8
9
3-FC6H4
C6H5
3,4-(OMe)2CH2C6H3
2-ClCH2C6H4
2-ClCH2C6H4
86
33
58
49
78
48
28
72
95
42
88
30.5
23
33
57.5
79
31
21
75
25
17
35
51.5
49.5
4-OMeC6H4
4-OHC6H4
3-ClC6H4
Cyclopropyl
4-ClC6H4
4-OHC6H4
Indolyl
4-OMeC6H4
3-NO2C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
–CH2C6H4
–CH2C6H4
–CH2C6H4
4-OMeC6H4
Napthyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2-ClCH2C6H4
3,4-(OMe)2CH2C6H3
2-OMeCH2C6H4
Ethylcyclohexane
5-Ethylbenzodioxole
3,4-(OMe)2CH2C6H3
5-Ethylbenzodioxole
3,4-(OMe)2CH2C6H3
C6H5
4-ClC6H4
4-OMeC6H4
4-ClC6H4
3,4-(OMe)2CH2C6H3
3-ClCH2C6H4
4-CF3CH2C6H4
3,4-(OMe)2CH2C6H3
Octyl
Hexadecyl
4-CF3CH2C6H4
Vinyl
4-OMeC6H4
4-OMeC6H4
4-OHC6H4
4-OHC6H4
4-ClC6H4
Vinyl
a
All the compounds were tested at a 30 lM concentration.
derivatives (1–30) and assessment of their PDE4 inhibitory activi-
ties revealed the importance of the substituents at the pendant
phenyl ring and pyridine nitrogen position of the DHP structure
on PDE4 inhibition. A comparison of the structure–activity rela-
tionships (SARs) for a number of compounds containing the dihy-
dropyridine ring were investigated for the in vitro inhibition of
PDE4. The most practical route for the synthesis of these com-
Figure 2. ORTEP representation of the compound 4, with the atom-numbering
scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms
are shown as small spheres of arbitrary radius.

R. R. Poondra et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1104–1109
1107
100
80
60
40
20
0
100
Compound 4
Compound 4
Compound 7
Compound 15
Compound 17
Compound 7
80
Compound 15
Compound 17
60
40
20
0
0.0001 0.001 0.01 0.1
1
10
100 1000
0.0001 0.001 0.01 0.1
1
10
100 1000
[Compounds]µM
[Compounds]µM
Figure 3. Dose–response curves of 4, 7, 15 and 17 with PDE4B and PDE4D.
Table 4
Table 3
Docking scores of synthesized inhibitors along with AMP and SI-15x
IC50 of selected compounds (greater than 50% inhibition)
S. No.
Compound ID
PDE4B
PDE4D
Compound
R1
R2
PDE4B IC50
PDE4D IC50
1
2
3
4
5
6
7
8
AMP
SI-15x
4
7
11
14
15
17
À11.4
À10.6
À7.5
À6.9
À6.8
À7.8
À8.1
À7.6
À11.0
À8.2
À5.7
À6.4
À5.8
À6.8
À7.0
À6.5
4
7
15
17
3,4-(OMe)2CH2C6H3
3,4-(OMe)2CH2C6H3
3,4-(OMe)2CH2C6H3
3,4-(OMe)2CH2C6H3
4-ClC6H4
3-FC6H4
Indolyl
3.71
4.22
0.54
1.57
2.78
3.33
0.65
2.89
3-NO2C6H4
100
IC50= 3.20 + 0.53 µM
80
60
40
20
0
sation between aldehyde, ethyl propiolate and the amine, heated
at 80 °C in glacial acetic acid afford the title compounds. In order
to obtain substitution at the C4-position, the aldehyde component,
was varied. Substitution at the N1-position was achieved by vary-
ing the benzylamine component. Good yields of the 1,4-DHPs were
obtained using a 15–30 min reaction time at 80 °C. All compounds
were purified through silica gel column chromatography and were
fully characterized by IR, 1H, 13C NMR and mass spectral analysis
(Supplementary data). Further, the single crystal X-ray diffraction
studies of four unambiguously confirmed their molecular struc-
tures (Fig. 2).
0.01
0.1
1
10
100
The synthesized derivatives (1À30) were tested for their inhib-
itory potencies against PDE4B and PDE4D using recombinant
isoenzymes as described in the supporting information. All the
[Compound 15] µM
Figure 4. TNF-
a
inhibition with compound 15.
compounds were tested at a fixed concentration (30 lM). The
functional group array of the scaffold and the percentage of PDE4B
inhibition for all the compounds at this concentration are shown in
Table 2. Several of the compounds tested showed promising PDE4B
inhibitory activity and dose response studies were undertaken to
determine IC50 of selected compounds which displayed greater
than 50% activity (Fig. 3 and Table 3).
In parallel, we also determined the selectivity of the selected
compounds against PDE4D and found that the selected compounds
exhibited similar potency against PDE4D as well. Elevation of
cAMP levels via inhibition of PDE4B is linked to a variety of anti-
inflammatory effects. Thus, compound 15 was tested for its ability
pounds incorporated the diversity at single-step stage, as shown in
Scheme 1, by treatment of aldehydes and with the appropriate
substituted primary amines.
The classical synthesis of symmetrical 1,4-DHPs is the three-
component cyclocondensation of aldehyde, b-ketoester and
ammonia in acetic acid or in alcohol, which was reported by Han-
tzsch.15 Despite the long history, sustaining interests in more
advanced synthetic methodology of 1,4-DHPs have been triggered
by the prolific pharmacological properties imbedded in 1,4-
DHPs.16 Recently much effort has been expanded to develop more
efficient methods for the preparation of 1,4-DHPs such as using
microwave,17 solvent free,18 metal triflates as catalyst,19 boronic
acids,20 ceric ammonium nitrate,21 and silica-supported acids.22
Here, the synthesis of substituted 1,4-dihydropyridines shown in
to blunt LPS-induced TNF-
a
production (Fig. 4) and was found to
M. Above set of exper-
inhibit TNF- synthesis with an IC50 of 3.2
a
l
iments revealed that compound 15 is the most potent amongst all
the compounds tested and is a suitable candidate for further
exploration.
Table
1
was accomplished by modification of the classical
To gather SAR information of the synthesized 1,4-DHP deriva-
tives, hit compound 9 was divided into two constituent parts and
Hantzsch reaction. Thus, three-component, one-pot cycloconden-

1108
R. R. Poondra et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1104–1109
Figure 5. Docked orientations of 15 in PDE4D (panel A and B), and in PDE4B (panel C).
modifications were systematically done at C4 and N1 positions. Ta-
ble 2 summarizes PDE4 inhibition data of C4 and N1-substituted
1,4-DHPs and clearly showed that 3,4-dimethoxybenzyl group (4,
7, 11, 15, 17, 22, and 25, >80% inhibition) were superior to other
substituents. In this series, the indole (15) and 3-nitrophenyl (17)
in PDE4D. The dimethoxy group interacts with the metal atoms
in PDE4B, while it is expected to interact with Gln443. The
Gln535 in PDE4D interacts with the dimethoxy group of 15. The in-
dole moiety of 15 in PDE4D makes strong H-bonding interactions
with Glu505 or Glu396 (in two possible orientations), while in
PDE4B, the same moiety is shown to interact in a H-bonded
manner with Ser442 backbone. This additional interaction of
indole moiety will make it a better inhibitor than the rest of the
synthesized inhibitors. The docking scores of 15 are marginally
better (i.e. lower) than the rest of the inhibitors, while further
rigorous molecular modeling studies may strengthen this
observation.
In conclusion, we have reported the first investigation of dihy-
dropyridine-based compounds on the PDE4 inhibition activity.
The dihydropyridine motif, bearing the dimethoxybenzyl and in-
dole groups form multiple interactions with the metal ion binding
site of PDE4, may also provide a new insights for the design of
PDE4 inhibitors. Further studies are ongoing to improve the selec-
tivity on PDE4 inhibition activity of our N-dimethoxybenzyl and
indole DHPs to optimize the inhibition profile.
moieties at C4 position (IC50 = 0.54 and 1.57 lM, respectively)
were more potent compounds. From the evaluated 1,4-DHPs, we
concluded that 4-phenyl and N-benzyl substitution of 1,4-DHPs
were important for PDE4 inhibitory activity, and we thus mainly
modified the R1 and R2 groups of the 1,4-DHP core. We found that
N-phenyl group abrogated PDE4 inhibition potency (18, 19 and
20). The conclusion was that an additional H-bond donor/acceptor
at R1 or R2 positions was required for potent PDE4 inhibitory activ-
ity, and this was supported by the lack of inhibition by 2, 6 and 27
(<20% inhibition), underscoring the assumption that an H-acceptor
at the N1-benzyl position were apparently required.
In order to gain further insight into the binding mode of 1,4-
DHPs with PDE4 enzymes, docking studies were carried out with
help of the Glide module Maestro (ver. 9.2), Schrodinger Inc.
according to the procedure described in the Supplementary data.
Studies were focused only on those compounds which showed
considerable inhibition on PDE4. Docking studies of the synthe-
sized inhibitors reveal significant understanding as to how they in-
hibit PDE4B and PDE4D enzymes. Table 4 reflects the docking
scores of the highest docking pose that has good conformational
consensus of AMP, standard inhibitor (SI-15x), and synthesized
compounds. It is apparent that the docking scores of most of these
molecules from Table 4 fall in similar range (i.e. within À5.7 to
À8.2) with PDE4B and PDE4D enzymes, thus giving evidence that
these compounds may serve as non-selective inhibitors.
Acknowledgments
We acknowledge financial support through Grant Nos. SR/S1/
OC-21/2011 (R.M.) and BT/PR12829/Med/30/222/2009 (M.P. and
K.V.L.P.) sponsored by DST and DBT, respectively, New Delhi, India.
R.V.N. thanks CSIR, New Delhi, India for the award of fellowship.
We also thank Professor Javed Iqbal and management of Institute
of Life Sciences (ILS) for constant encouragement and support.
Supplementary data
The variations within the measured activity may not be re-
flected from the docking scores; nevertheless, a greater under-
standing of relative inhibitory potency of the synthesized
inhibitors lies in their critical interactions within the enzyme—
while the differences among the active sites and shapes of PDE4B
and PDE4D determine selectivity. The docked orientations of some
synthesized inhibitors along with the SI-15x are given in Supple-
mentary data.
Inhibitor 15 gave best docking score in PDE4B (À8.1) and
PDE4D (À7.0) among other inhibitors its relative sensitivity to-
wards inhibition of these two enzymes, as shown in Table 4. Figure
5 depicts the two possible docked orientations of 15 in PDE4D
(panels A and B), while a single possible interacting orientation
in PDE4B (panel C). The indole moiety of 15 forms two possible
orientations in PDE4D, and in both cases, it makes a stronger
hydrogen bond with the residues Glu396 or Glu505 of PDE4D,
while its orientation in PDE4B is completely different than that
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
11.121.
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