The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.07.076

The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC₅₀ = 0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized.

Full text of DOI:10.1016/j.bmcl.2010.07.076

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5502–5505
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The discovery and synthesis of highly potent subtype selective
phosphodiesterase 4D inhibitors
*
Renee Aspiotis , Denis Deschênes, Daniel Dubé, Yves Girard, Zheng Huang, France Laliberté, Susana Liu,
Robert Papp, Donald W. Nicholson, Robert N. Young
Merck Frosst Centre for Therapeutic Research, 16711 Trans-Canada Hwy, Kirkland, Québec., Canada H9H 3L1
a r t i c l e i n f o
a b s t r a c t
Article history:
The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of
the series led to the discovery of compound 26b, a highly potent (IC50 = 0.6 nM) and selective PDE4D
inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against
other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 1 June 2010
Revised 14 July 2010
Accepted 16 July 2010
Available online 21 July 2010
Keywords:
PDE4D
Phosphodiesterase 4D inhibitors
Asthma
COPD
Quinoline
The phosphodiesterases (PDEs) are metallo hydrolases responsi-
ble for the degradation of the secondary messengers adenosine and
guanosine 30,50-cyclic monophosphates (cAMP and cGMP, respec-
tively).1 Comprised of multiple isoforms, the PDEs are classed into
11 families (PDE1-11) according to their substrate specificities,
tissue and subcellular distribution, amino acid sequences, and
response to exogenous and endogenous substrates.1,2
Among the most targeted PDEs are the type 4 cAMP-specific
phosphodiesterases (PDE4s), the predominant isoenzyme in air-
way smooth muscle cells as well as immune and inflammatory
cells.3 There are four genes comprising the PDE4 family, PDE4A,
PDE4B, PDE4C, and PDE4D and all are expressed as multiple splice
variants. Inhibition of this family of enzymes significantly in-
creases intracellular cAMP levels, leading to the down regulation
of various cytokines and proinflammatory mediators, and the
suppression of infiltration of neutrophils and eosinophils in in-
flamed airways.4 Indeed, several PDE4 drug candidates have been
identified as promising anti-inflammatory agents for the treatment
of asthma, chronic obstructive pulmonary disease (COPD), and
rheumatoid arthritis, including the archetype rolipram and its
second generation inhibitors cilomilast and roflumilast.5
mice together with siRNA targeting and distribution studies dem-
onstrate that the PDE4 subtypes have distinct functional roles in
inflammatory, immunocompetent, and smooth muscle cells.7 Tar-
geting one of the four subtypes thus may be advantageous in max-
imizing the therapeutic window of efficacy over its reported
adverse effects.
Within the last decade, considerable effort has been directed
toward understanding the biological role of PDE4D. PDE4D
accounts for at least 80% of PDE activity in inflammatory cells.8
In knockout mice, the PDE4D gene was directly associated with
potent anti-inflammatory effects and the loss of airway hyperactiv-
ity.9 In humans, a genome-wide association analysis identified
PDE4D as an asthma-susceptibility gene.10 PDE4D has also been
implicated in depression11, long-term memory formation12, pros-
tate cancer13, Type II diabetes14, cystic fibrosis15, and controver-
sially in stroke.16 One potential caveat of PDE4D inhibition is its
proposed association with the central nervous system-related
emesis and cardiac side effects.17 While it is not entirely clear
whether PDE4D inhibition alone is the sole basis of the said ad-
verse events, its emerging therapeutic potential prompted us to
begin a medicinal chemistry effort to identify a subtype selective
PDE4D inhibitor.
A key obstacle limiting the practical application of PDE4 inhib-
itors is their reported dose-limiting side effects, namely nausea and
emesis.6 All of the earlier chemotypes do not discriminate between
the PDE4 subtypes (A, B, C, or D), yet recent studies from knockout
Examples of PDE4D selective inhibitors have been reported in
the literature (Fig. 1). The prototypical example is Cilomilast 1 with
a ꢀ7-fold reported selectivity for the D subtype (IC50 = 12 nM)
relative to PDE4A, B and C.19a Nicotinamide 2 has also been shown
to be a potent subtype selective PDE4D inhibitor with a minimum
140-fold selectivity over its respective subtypes.15 In addition,
* Corresponding author.
E-mail address: renee_aspiotis@merck.com (R. Aspiotis).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.076

R. Aspiotis et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5502–5505
5503
O
O
Me
COOEt
COOH
COOH
b, c
a
N
COOH
N
H
N
H2N
OMe
Br
Br
O
CN
OMe
O
Me
6
7
8
F
1 (Cilomilast, Ariflo, SB 207 499)
2
d, e
Me
Me
6
O
Br
R
f
Me
S
O
N
N
COOH
O
N
8
6
HO
R
N
OMe
OMe
N
N
N
8
3'
9
R = 4-CH2COOMe, 10
= 2-Cl, 11
N
Me
= 3-Cl, 12
3'
OMe
O
= 4-CF3, 13
N
N
MeSO2
= 4-CH2CH2CN, 14
N
O
3 (NVP-ABE171)
4
(L-454,560)
5
Scheme 1. Reagents and conditions: (a) glycerol, 3-NO2PhSO3Na, H2SO4/H2O, heat;
(b) EtOH, H2SO4, reflux; (c) 3-MeOC6H4B(OH)2 Pd(dppf)Cl2 (cat.), Na2CO3, EtOH/tol
(1:1), reflux; (d) LiAlH4, THF, ꢁ78 °C; (e) HBr, HOAc, 100 °C; (f) Cs2CO3, DMF, rt, o/n.
Figure 1.
Hersperger et al. have developed potent, subtype selective D inhib-
itors such as 3 (NVP-ABE171) which has activity in both human
inflammatory cells and in in vivo models of lung inflamma-
tion.18b,18c Our quest for a PDE4D selective inhibitor stemmed from
the simple pyridylmethylquinoline 519 which was shown to be a
potent pan-selective PDE4 inhibitor. We were intrigued by the fact
that this truncated version of our initial clinical candidate 4 (L-
454,560)19b retained much of its activity on the D subtype relative
to B (twofold loss in D vs fivefold loss in B, Fig. 1 and Table 1). A
library was thus set out to further explore the 6- and 8-position
of the quinoline core in hope that we could gain additional selec-
tivity and binding with respect to the D subtype. Herein, we wish
to report the discovery of 6-aryloxymethyl-8-aryl substituted
quinolines as a new structural class of potent, subtype selective
PDE4D inhibitors.
The syntheses of 419b and 519a have been previously described.
Access to the quinoline compounds 10–14 can be similarly ob-
tained as illustrated in Scheme 1. Thus, treatment of commercially
available aniline 6 with excess glycerol under Skraup conditions
afforded the corresponding 6-carboxy-8-bromoquinoline interme-
diate 7. A direct Suzuki coupling on this intermediate proved prob-
lematic upon scaling so the crude acid 7 was converted to its ethyl
ester using standard Fischer conditions. A subsequent Suzuki cou-
pling with commercially available 3-methoxyphenyl boronic acid
using Pd(dppf)Cl2 catalyst easily afforded the 30-methoxy-8-aryl-
quinoline intermediate 8. Careful reduction of the ethyl ester with
LiAlH4 at ꢁ78 °C followed by conversion to the methylbromide
intermediate 9 set the stage for the final alkylation step, in which
treatment with an appropriately substituted phenol using Cs2CO3
Table 1
Potency and selectivity profiles of PDE4 inhibitors against the four human subtypes A,
B, C, and D
a,b
Compound
IC50 (nM)
Ratio B/D
PDE4A
PDE4B
PDE4C
PDE4D
5
4
1.5
1.4
9.9
4.6
2.3
0.5
10.7
7.4
87
389
418
86.5
120
96.3
92.7
43.3
369
57.6
15.3
8.7
3.3
9.1
2.5
1.2
9.3
0.4
0.9
0.4
1.2
18
17
32
9
44
5
6
27c
10
11
12
13
14
18
19
20
21
22
23
24
25b
26b
69.5
31.2
469
102.1
218
126
319
338
122
307
350
224
166
819
60.4
12.8
5.7
5.0
12.1
48.7
2.0
22.2
17.0
10.5
4.5
18.3
0.9
0.8
414
R1
1977
28,300
1235
1115
1341
103
36.2
32.2
151
Br
Me
O
9
c
10
20
61
20
36
75
d
a,b
H2N
R1
N
Br
N
Br
16
Br
17
HO
0.2
0.6
15
63.7
45.0
R1
a
b
c
Values are means of at least two experiments.
See Ref. 22 for assay conditions against the PDE4 subtypes.
Structure of compound 27.
O
R1 = 4-CH2CH2CN,
R2 = H, 18
= OCF3, 19
= F, 20
or
R
2 = OCHF2,
R1 = -SO2Me, 24
Me Me
N
= -CH2COOMe, 25a
= -CH2COOH, 25b
= -CH2CH2COMe 26a
Me
e
S
O
O
= OEt, 21
f
R2
N
= -CH2CH2COH(CH3)2, 26b
= Me, 22
= OCHF2, 23
OMe
Scheme 2. Reagents and conditions: (a) glycerol, FeSO4ꢂ7H2O, MeSO3H, 3-NO2Ph-
SO3Na, 130–135 °C; (b) Vazo-52Ò, NBS, chlorobenzene, 50 °C; (c) Cs2CO3, DMF,
50 °C; (d) 3-substituted phenyl boronic acid or pinacol boronate ester, Pd(dppf)Cl2
(cat.), Na2CO3, DMF, 90 °C; (e) LiOH, THF, MeOH, 50 °C; (f) MeLi, CeCl3, THF, ꢁ78 °C–
rt, 4 h.

5504
R. Aspiotis et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5502–5505
2.5
2
as the base in DMF afforded the desired phenolic ether analogs 10–
14.
2.04
A more convergent method of accessing 6-aryloxymethyl-8-aryl
substituted quinolines 18–26 is depicted in Scheme 2. The bro-
momethylquinoline starting material 16 was synthesized in two
steps using an optimized process route by condensing 2-bromo-
4-methylaniline 15 with glycerol followed by a radical bromina-
tion of the corresponding 6-methyl-8-bromoquinoline.20 Subse-
quent displacement of the intermediate bromomethylquinoline
16 with an appropriately functionalized 4-substituted phenol fol-
lowed by standard Suzuki coupling using either a commercially
available boronic acid or a pre-synthesized pinacol boronate ester,
as in the case for R2 = OCHF2, afforded compounds 18–26. Hydroly-
sis of the methyl ester 25a with LiOH afforded the final acid 25b,
whereas the tertiary alcohol 26b was easily obtained by reacting
methyl ketone 26a with a methyl cerium reagent derived from
MeLi and CeCl3.
1.37
1.5
1
0.77
0.5
0
BLOQ
< 5nM
0.15
0.13
Figure 2. Tissue, CSF and plasma levels of compound 26b 1 h post-interperitoneal
dosing in fasted male Wistar–Han rats (n = 2). Dose = 3 mg/kg, dose volume = 3 mL/
kg in 60% PEG200 (Ref. 23).
All of the compounds were evaluated for their inhibitory activ-
ity against the four subtypes PDE4A, B, C, and D (Table 1).22 For
comparison, the data for 4 and 5 are also included.19b The B/D ratio
was used as a selectivity gauge as the catalytic active sites of these
two subtypes are said to be most comparable.21
Preliminary pharmacokinetic testing demonstrated oral bio-
availability in rats with F = 25%, Vdss = 4.87 L/kg, CL = 44 mL/min/
kg, and t1/2 = 3.5 h.23 Drug levels were also assessed in a panel of
tissues where PDE4D activity may play a physiologically important
role (Fig. 2). In summary, compound 26b exhibited favorable distri-
bution to tissues relative to plasma 1 h post-interperitoneal dosing,
with high levels noted in the liver, prostate, and heart (2.04, 1.37,
Previous work toward the design of 4 (L-454,560) revealed that
the bulky 30 substituent could be replaced with a smaller methoxy
group with an average ꢀ10-fold loss in intrinsic potency across the
four PDE4 subtypes (compound 4 vs 27). Interestingly, potency
across the four subtypes could be restored with a 6-pyridylmethyl
substituent as depicted in 5. A closer observation of the overall loss
in potency on going from 4 to 5 suggested that the D subtype was
less affected by the change in the 6-position on the quinoline ring
compared to the B subtype (twofold loss in D vs fivefold loss in B).
This subtle finding prompted us to further explore the 6-position of
the quinoline ring in hope that the compound’s affinity for the B
subtype could be tuned out; the bromomethylquinoline intermedi-
ate 9 served as a useful tool for this purpose.
Many thio, sulfinyl, sulfonyl, and alkoxy ethers were synthe-
sized, of which the phenolic ether template prevailed (Table 1,
compounds 10–14). In particular, a para-phenolic ether bearing a
2-cyanoethyl moiety 14 was deemed most interesting in terms of
its potency (2.0 nM) and selectivity for the D subtype (44-fold over
B). We then decided to further optimize the 30 position on the
8-aryl ring of the quinoline core (compounds 18–23), keeping the
substituents small, and quickly found that a difluoromethoxy sub-
stituent 23 was a suitable replacement for the methoxy analog in
14. A further reoptimization of the 2-cyanoethyl moiety in the
quinoline compound 23 afforded subnanomolar PDE4D inhibitors
24, 25b, and 26b with moderate to good 4D selectivity. In particu-
lar, the highly potent tertiary alcohol 26b (0.6 nM) proved most
interesting with an observed 75-fold selectivity for PDE4D.
Compound 26b was further profiled against a panel of PDE
family members and was shown be a highly specific PDE4D inhib-
itor, with a minimum 18,000-fold selectivity for the 4D isoform
(Table 2).
and 0.77 lM, respectively). Interestingly, PDE4D has been shown
to be over-expressed in human prostate cancer tissues and cell
lines. Moreover, PDE4D can be selectively knocked down with shR-
NAs resulting in the reduction of growth and proliferation of pros-
tate cancer cells in vivo and in vitro.13 Thus, a subtype selective
PDE4D inhibitor such as 26b may serve as a useful tool in deter-
mining the potential of PDE4D inhibitors as anti-prostate cancer
agents.
In summary, we have identified highly potent and selective
inhibitors of PDE4 targeting the D subtype. The 6-bromomethyl-
8-bromoquinoline intermediate 16 served as a useful tool in rap-
idly addressing substituents at both the 6- and 8-position of the
quinoline core. The tertiary alcohol 26b was found to be most
interesting, with an IC50 = 0.6 nM on PDE4D, a 75-fold selectivity
over the subtypes A, B, C and over 18,000-fold selectivity against
other PDE family members. Future studies using this compound
as a biological tool may further delineate the biological relevance
of inhibiting PDE4D in vitro and in vivo.
Acknowledgments
The author thanks Dr. Michel Gallant and Dr. David Powell for
helpful discussions and the proof reading of the manuscript. In
addition, Dr. Izzat Raheem is thanked for helping with the profiling
of compound 26b against other PDE family members.
References and notes
Table 2
Potency and selectivity profile of compound 26b against a panel of
human PDE family members
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