CDP840. A prototype of a novel class of orally active anti-inflammatory phosphodiesterase 4 inhibitors

Article abstract of DOI:10.1016/S0960-894X(02)00202-0

The discovery, synthesis and biological activity of a series of triarylethane phosphodiesterase 4 inhibitors is described. Structure-activity relationship studies are presented for CDP840 (29), a potent, chiral, selective inhibitor of PDE 4 (IC₅₀

Full text of DOI:10.1016/S0960-894X(02)00202-0

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1451–1456
CDP840. A Prototype of a Novel Class of Orally Active
Anti-Inflammatory Phosphodiesterase 4 Inhibitors
R. P. Alexander,a,* G. J. Warrellow,a M. A. W. Eaton,a E. C. Boyd,a J. C. Head,a
J. R. Porter,a J. A. Brown,a J. T. Reuberson,a B. Hutchinson,a P. Turner,a B. Boyce,a
D. Barnes,a B. Mason,a A. Cannell,a R. J. Taylor,a A. Zomaya,a A. Millican,a
J. Leonard,a R. Morphy,a M. Wales,b M. Perry,b R. A. Allen,b N. Gozzard,b B. Hughesb
and G. Higgsb
aDepartment of Medicinal Chemistry, Celltech R&D Ltd., 208 Bath Road, Slough, Berkshire SL1 3WE, UK
bDepartment of Biology, Celltech R&D Ltd., 208 Bath Road, Slough, Berkshire SL1 3WE, UK
Received 20 December 2001; revised 27 February 2002; accepted 26 March 2002
Abstract—The discovery, synthesis and biological activity of a series of triarylethane phosphodiesterase 4 inhibitors is described.
Structure–activity relationship studies are presented for CDP840 (29), a potent, chiral, selective inhibitor of PDE 4 (IC50 4 nM).
CDP840 is non-emetic in the ferret at 30 mg kgÀ1 (po), active in models of inflammation and reverses ozone-induced bronchial
hyperreactivity in the guinea pig. # 2002 Elsevier Science Ltd. All rights reserved.
Cyclic nucleotides play a key role in cell function by
acting as intracellular secondary messengers, relaying
the signals from hormones acting at specific cell-surface
receptors.1 Phosphodiesterases (PDEs) are a super-
family of 11 isoenzymes2 responsible for the hydrolysis
of cAMP and cGMP.3 Elevation of cAMP levels by stim-
ulation of adenylyl cyclase or by inhibition of PDEs,
exerts a broad inhibitory effect on the activity of
immune and inflammatory cells.4 PDE 4, a cAMP spe-
cific PDE, has attracted particular attention as a target
for the treatment of diseases such as asthma and COPD
due to its distribution in most immune and inflamma-
tory cells and airway smooth muscle.5 The utility of the
first generation of PDE 4 inhibitors (e.g., rolipram 1)
has been severely curtailed due to dose limiting side
effects such as nausea and vomiting,6 psychotropic
activity7 and increased gastric secretion.8
We set out to produce a novel, potent and selective ser-
ies of inhibitors devoid of these side effects. Exploring
the SAR around rolipram (1) provided several series of
PDE 4 inhibitors,9 which ultimately led to the tri-
arylethanes. Three approaches (Schemes 1–3) were used
to synthesize the triarylethanes. Our initial synthetic
efforts were directed towards optimization of the group
in the 1 position of the ethane as illustrated by the
reaction sequence shown in Scheme 1.10 Alkylation of
isovanillin (2) with cyclopentyl bromide in DMF pro-
duced the derivative (3). Reaction with phenyl lithium
furnished the diaryl methanol (4) which was subsequently
oxidized with activated manganese dioxide yielding the
benzophenone (5). Reaction with the anion of 4-methyl
pyridine gave the alcohol (6) which was then converted
to the alkene (7) by acid catalyzed elimination. Catalytic
hydrogenation provided the desired triaryl ethane (8).
A complimentary synthesis is exemplified by the reac-
tion sequence shown in Scheme 2. Olefination of ben-
zophenone (5) gave the alkene (9). Heck reaction with
an aryl halide yielded the trisubstituted alkene (10), as a
mixture of double bond isomers. Catalytic hydrogena-
tion provided the triarylethane (11). The 1-ethane sub-
stituent was varied to ascertain the optimal group.
Table 1 shows that the 4-pyridyl group is optimal of the
groups studied. Removal of the aromaticity to give com-
pound 14 leads to a complete loss of activity. Attempts to
*Corresponding author. Tel.: +44-1753-534655; fax: +44-1753-
536632; e-mail: rikki.alexander@celltechgroup.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00202-0

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R. P. Alexander et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1451–1456
Table 1. SAR for the 1-ethane group
Compd
R
Inhibition of PDE 4A (yeast) IC50 (nM)
17.5
8
11
12
13
14
15
16
17
1170a
172
Scheme 1. Reagents and conditions: (a) c-C5H9Br, Cs2CO3, DMF,
95%; (b) PhLi, THF, 99%; (c) MnO2, CH2Cl2, 85%; (d) LDA, 4-
MePy, THF, 90%; (e) TsOH, PhMe, 100%; (d) Pd/C, H2, EtOH,
90%.
40
>8000a
40
Scheme 2. Reagents and conditions: (a) MePPh3Br, LDA, THF, 97%;
(b) Pd(OAc)2, (o-Tolyl)3P, Et3N, PhBr; 35%; (c) Pd/C, H2, EtOH,
95%.
389
423a
aInhibition of PDE 4A (yeast), Ki (nM).
Table 2. Effect of substituent position on 2-phenyl group
Compd
R
Inhibition of PDE 4A (yeast)
IC50 (nM)
18
19
20
21
22
23
ortho-OMe
meta-OMe
para-OMe
ortho-F
meta-F
para-F
259
58
17
158
8
Scheme 3. Reagents and conditions: (a) Ethyl 4-pyridylacetate, TsOH,
piperidine, PhMe, 58%; (b) (1) NaOH, (2) SOCl2; (c) Sultam, THF,
67% (2 steps); (d) PhMgBr, THF, 76%; (e) LiSPr, THF; (f) NaOH,
HCl, 82% (2 steps).
47

R. P. Alexander et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1451–1456
1453
replace the 4-pyridine with other heterocycles leads to a
loss in activity, the 4-pyrimidine, (13) and the 5-(1-
methyl) imidazole (15) being the next most active.
Attempts to mimic the pyridine ring with a substituted
benzene ring leads to a significant loss in potency. Table
2 shows the effect of moving a substituent around the
phenyl group in the 2 position of the ethane. Whilst
meta and para substitution retain potency, substitution
in the ortho position leads to a loss of activity, for both
the methoxy and the fluorine substituents. This sug-
gested that the meta and para positions were more tol-
erant of substitution and an exploration of the SAR
associated with these positions could be useful in the
pursuit of more potent compounds.
nitrogen of the urea show the least drop off in activity
between isolated enzyme assay and human whole blood
assay. Whilst 54 and 56 are equipotent in inhibiting
LPS-stimulated TNF-a in human whole blood, 56
shows only a 16-fold differential between the two assays.
Other functionality is tolerated at the meta position as
illustrated by the sulfuric diamide 57 and the ether 58.
Peracetic acid oxidation of CDP840, 29, Scheme 4, gives
the pyridine N-oxide, 59, in 97% yield. 59 showed simi-
lar activity to the parent compound in inhibiting PDE 4
(IC50 7 nM) and TNF-a production (IC50 6.6 mM).
Whilst the pyridine ring is required for activity, the
basic nitrogen atom is not.
CDP840, 29, was profiled in models of pulmonary eosino-
philic inflammation and antigen-induced broncho-
constriction. CDP840, 29, caused a dose dependent
reduction of IL-5-induced pleural eosinophilia in rats
(ED50=0.03 mg kgÀ1) when dosed orally. The eosino-
phils in pleural exudates from CDP840-treated animals
contained higher levels of eosinophil peroxidase (EPO)
than cells from control animals, suggesting a stabilizing
effect on eosinophil degranulation.14 Antigen-induced
pulmonary eosinop-hilia in sensitized guinea pigs was
reduced in a dose-dependent way by CDP840, (ED50=
0.1 mg kgÀ1) and intracellular EPO levels were sig-
nificantly higher.15 In sensitized guinea pigs, aerosols of
An asymmetric synthesis of this class of compounds was
required, (Scheme 3).11 Knovenagel condensation of
ethyl 4-pyridylacetate with aldehyde 3 gave the cinna-
mate 24. Base hydrolysis of the ester resulted in the acid,
which was converted to the acid chloride 25 with thionyl
chloride. Reaction with the sodium salt of (2S)-bor-
nane-2,10-sultam gave the acyl sultam 26. Michael
reaction12 with phenylmagnesium bromide gave, after
crystallization, the product 27 as a single diastereo-
isomer.11 Removal of the sultam was achieved using
lithium thiopropiolate. The thioester 28 was hydrolyzed
with base and the acid removed by decarboxylation to
give the triarylethane 29, CDP840, in greater than
99.5% ee. This chiral synthesis of the eutomer of 8, 29,
allowed assignment of its stereochemistry as R by X-ray
analysis of the intermediate 27.
the antigen ovalbumin caused
a dose-dependent
bronchoconstriction demonstrated by an increase in
pulmonary inflation pressure. Administration of
CDP840, (ED50=1.0 mg kgÀ1, ip), 1 h before antigen
challenge, resulted in a dose-dependent reduction in
response to antigen.14 CDP840 (ED50=0.01 mg kgÀ1 ip)
dose relatedly inhibited ozone-induced hyperreactivity
to histamine in guinea pigs.15 CDP840 was non-emetic
in ferrets at doses up to 30 mg kgÀ1 (po). CDP840 when
dosed at 15 mg b.i.d. to asthmatic patients for 9.5 days
attenuated the late phase asthmatic response to allergen
challenge by 30% in the absence of any bronchodilatory
or histamine antagonist effect.16 This suggests that
CDP840 may exert its effects via an anti-inflammatory
mechanism. It was also shown to be devoid of the side
effects normally associated with PDE 4 inhibitors at
single oral doses of up to 64 mg.
This synthetic route facilitated an exploration of the
SAR associated with the phenyl group and a compar-
ison of the enantiomers of 8. The potency against PDE
4 and ability to inhibit the LPS-stimulated TNF-a pro-
duction in human whole blood,13 a measure of cellular
efficacy, of this series is reported in Table 3. CDP840,
29, has an IC50 against PDE 4 of 4 nM, but its ability to
inhibit LPS-induced TNF-a production in human whole
blood is 8.5 mM, representing a 2125-fold drop of in
activity. CDP840, 29, is an exceptionally selective PDE
4 inhibitor, having an IC50 against PDEs 1, 2, 3, 5 and 7
of greater than 10,000 nM. The distomer of 8, 30, is over
30-fold less active against PDE 4, although this differ-
ential is reduced to 3-fold when inhibiting LPS-stimu-
lated TNF-a formation in human whole blood when
compared to the eutomer, 29. PDE 4 is tolerant of a
wide range of groups in the 2 position of the ethane.
Both aromatic and heteroaromatic groups give potent
compounds. A series of para substituted sulfonamides
was synthesized, compounds 36 to 42. The cyclic
sulfonamide, 42, was the most potent compound against
the isolated enzyme. However, the pentafluorophenyl
sulfonamide 41 is the most potent inhibitor of TNF-a
production in that series, showing only a 19-fold drop
off in activity in the whole blood assay. Other function-
ality was accommodated in the para position. Ureas and
amides gave potent compounds. A series of meta sub-
stituted ureas was synthesized, compounds 47 to 56.
Compound 49 (CT 2450) is the most potent inhibitor of
the isolated enzyme, having an IC50 of 0.3 nM. How-
ever, compounds that are disubstituted on the terminal
In summary a novel triarylethane series of potent,
selective PDE 4 inhibitors was discovered. The proto-
type member of this series, CDP840, 29, was shown to
reduce antigen-induced bronchoconstriction and pul-
monary eosinophilic inflammation in animal models
and attenuate the late phase asthmatic response to
allergen challenge in patients. These results suggest that
Scheme 4. Reagents and conditions: (a) CH3CO3H, CH2Cl2, 97%.

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R. P. Alexander et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1451–1456
Table 3. SAR for group in ethane 2 position
Compd
Ra
Inhibition of PDE 4A (yeast) IC50 (nM)
4
HWB (TNF-a) IC50, mMb
29
8.5
30
148
27.6
31
32
8
5
6.5
5.9
33
34
3
11.8
6.9
68
35
36
5
6.9
2.2
2.5
37
9
2.2
38
39
40
41
42
7
1.8
7
4.7
8
2.5
7.5
0.8
0.14
0.51
(continued on next page)

R. P. Alexander et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1451–1456
1455
Table 3 (continued)
Compd
Ra
Inhibition of PDE 4A (yeast) IC50 (nM)
4.8
HWB (TNF-a) IC50, mMb
43
22.9
44
45
46
47
48
49
50
51
52
53
54
55
56
57
4
11
7.3
8.7
10.5
2.7
5.2
2.5
8.1
12.8
3.1
4.3
0.3
2.3
0.3
6.4
10
22
19
0.3
54.6
113
31
137
16
27
5
12
58
102
6.4
aAll compounds are chiral, ee >99.5%.
bInhibition of LPS-induced TNF-a in human whole blood (HWB).13

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R. P. Alexander et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1451–1456
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active prophylactic treatment for asthma or other
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Acknowledgements
We are indebted to Dr D. J. Williams of Imperial Col-
lege London for the crystal structure of 27.
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