7-Methoxyfuro[2,3-c]pyridine-4-carboxamides as PDE4 inhibitors: A potential treatment for asthma

Article abstract of DOI:10.1016/S0960-894X(01)00786-7

The synthesis and pharmacological profile of a novel series of 7-methoxy-furo[2,3-c]pyridine-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4). Initial

Full text of DOI:10.1016/S0960-894X(01)00786-7

Bioorganic & Medicinal Chemistry Letters 12 (2002) 509–512
7-Methoxyfuro[2,3-c]pyridine-4-carboxamides as PDE4
Inhibitors:A Potential Treatment for Asthma
George M. Buckley, Nicola Cooper, Richard J. Davenport, Hazel J. Dyke,
Fiona P. Galleway, Lewis Gowers, Alan F. Haughan, Hannah J. Kendall,
Christopher Lowe, John G. Montana, Janet Oxford, Joanna C. Peake, C. Louise Picken,
Marianna D. Richard, Verity Sabin, AndrewSharpe* and Julie B. H. Warneck
Celltech R & D, Granta Park, Great Abington, Cambridge CB1 6GS, UK
Received 7 September 2001; revised 12 November 2001; accepted 20 November 2001
Abstract—The synthesis and pharmacological profile of a novel series of 7-methoxy-furo[2,3-c]pyridine-4-carboxamides is described.
Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4). Initial # 2002 Elsevier Science
Ltd. All rights reserved.
Phosphodiesterase type 4 (PDE4) is a cAMP-specific
phosphodiesterase present in inflammatory cells and
airway smooth muscle. It catalyses deactivation of
cAMP by hydrolysis of the phosphodiester bond. The
elevated levels of cAMP which result from inhibition of
PDE4 cause activation of the protein kinases respon-
sible for decreasing inflammatory cell activity and air-
way smooth muscle tone. This leads to suppression of
inflammatory cell functions and relaxation of airway
smooth muscle.1 These effects have prompted the inves-
tigation of PDE4 inhibitors as a potential treatment for
asthma.2 The first selective PDE4 inhibitor to be identi-
fied was rolipram,3 which also caused side effects of
nausea and emesis. It has been postulated that in addi-
tion to binding to the catalytic site on the enzyme, roli-
pram also binds to a high affinity site (known as the
rolipram binding site)4 and it is believed that the emetic
side effects correlate with this binding.5 Modifications to
the structure of rolipram have been carried out to iden-
tify novel PDE4 inhibitors devoid of side effects. To
date, the most advanced PDE4 inhibitor is cilomilast
(Ariflo, SB-207499), which is now in phase III trials in
the clinic.6
Our objective was to identify PDE4 inhibitors with
good selectivity for the catalytic site over the rolipram
binding site. Since inhibition of PDE3 may result in
cardiotoxicity, selectivity for PDE4 over the PDE3 iso-
zyme is also important.7
The preparation of a series of PDE4 inhibitors in which
the 3,4-dialkoxyphenyl unit is replaced with a 7-meth-
oxybenzofuran has been previously reported.8,9 Here we
describe the replacement of the 7-methoxybenzofuran
with 7-methoxyfuro[2,3-c]pyridine to generate a novel
series of inhibitors. Incorporation of the nitrogen atom
was intended to improve the pharmacokinetic proper-
ties of this series over the benzofurans. A variety of
substituents have been incorporated at the 2-position of
the furopyridine to investigate their effect on potency
and selectivity. Some work has also been undertaken to
investigate the effect of replacing the 3,5-dichloropyridyl
with other six-membered aromatic rings.
*Corresponding author. Fax: +44-1223-896400;
e-mail: andrewsharpe@celltechgroup.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00786-7

510
G. M. Buckley et al. / Bioorg. Med. Chem. Lett. 12 (2002) 509–512
Following the procedure of Shiotani and Morita,10
commercially available furan-3-acrylic acid 1 was
treated with isobutyl chloroformate and triethylamine
in acetone to give a mixed anhydride, which was
converted to acyl azide 2 by reaction with sodium
azide. Heating acyl azide 2 with tributylamine in
diphenylmethane at 180 ꢀC afforded furo[2,3-c]pyridin-
7(6H)-one 3. This was converted to the desired 7-meth-
oxyfuro[2,3-c]pyridine 4 via the 7-chloro derivative by
refluxing with phosphorus oxychloride followed by
treatment with sodium methoxide in 1,4-dioxane
(Scheme 1).
with methyl iodide and sodium hydride gave the
methoxymethyl analogue 5b. Similarly using N-Boc-
protected 4-piperidinone as the electrophile resulted
in 4-methoxy-4-(7-methoxyfuro[2,3-c]pyridin-2-yl)-piper-
idine-1-carboxylic acid tert-butyl ester 5c. The
cyclic ethers 5d and 5e were prepared using tetrahydro-
4H-pyran-4-one and dihydrofuran-3-one respectively
in the initial anion reaction. Treatment with mesyl
chloride and triethylamine followed by hydrogen-
ation using Raney nickel gave the desired products.
2-Bromofuro[2,3-c]pyridine was prepared by reaction
of the anion with bromine. This intermediate was
converted to the 2-pyridyl derivative 5f via a pal-
ladium-catalysed Suzuki reaction with (3-pyridyl)-
borane.
Once the 2-substituent was in place, the various inter-
mediates were further elaborated to the desired final
compounds using the same set of reaction conditions.
Thus, the 4-bromo-7-methoxy-furo[2,3-c]pyridines 6
were prepared by treatment of compounds 5 with N-
bromosuccinimide. Carbonylation followed by 4-nitro-
phenyl ester formation afforded key intermediates 7.
These were coupled with the anion of 4-amino-3,5-
dichloropyridine-N-oxide (preformed using sodium
hydride in DMF) to give our novel series of test com-
pounds 8 (Scheme 2).
These were screened in our in vitro assay (Table 1).
Scheme 1. Reagents and conditions: (i) C1CO2CH2CH2(CH3)2, NEt3,
acetone; (ii) NaN3, H2O; (iii) NBu3, Ph2CH2, 180 ꢀC; (iv) POCI3: (v)
NaOMe, 1,4-dioxane.
The preparation of the required 2-substituted furopyri-
dines was achieved in a variety of ways. Treatment of 7-
methoxyfuro[2,3-c]pyridine 4 with n-butyl lithium and
ethyl iodide afforded 2-ethyl-7-methoxyfuro[2,3-c]pyri-
dine 5a. Forming the anion at the 2-position of
the furopyridine in the same way and subsequent
treatment with formaldehyde followed by reaction
Scheme 2. Reagents and conditions: (i) NBS, MeCN; (ii) CO,
Pd(OAc)2, bis-diphenylphosphinopropane, NEt3, THF, H2O; (iii) p-
.
nitrophenol, EDC HC1, DMAP, CH2Cl2; (iv) 4-amino-3,5-dichlor-
opyridine-N-oxide, NaH, DMF.

G. M. Buckley et al. / Bioorg. Med. Chem. Lett. 12 (2002) 509–512
Table 1. 2-Substituted furo[2,3-c]pyridinesa
511
Table 3. N-Heterocyclo-2-ethylfuro[2,3-c]pyridinyl-4-carboxamidesa
PDE3b
(%)
11
12
11
12
PDE4 IC50
RBA IC50
PDE4/RBA
PDE3b
(%)
PDE4 IC50
RBA IC50
PDE4/RBA
Rolipram
3.5
0.02
175
27
32
IA
IA
3
8a
11a
11b
11c
11d
11e
11f
0.014
0.12
0.12
21%
0.14
0.066
0.23
0.084
0.28
0.35
NT
0.27
0.27
0.58
0.16
0.45
0.33
NA
0.49
0.24
0.39
32%
39%
NT
NT
IA
8a
8b
8c
8d
8e
8f
0.014
0.047
0.048
0.047
0.023
0.062
0.084
0.280
1.01
0.295
0.151
0.621
0.16
0.17
0.05
0.16
0.15
0.10
NT
NT
NT
NT
aValues are shown as IC50 (mM) or percent inhibition at 20 mM and are
the means of at least two experiments. RBA, rolipram binding assay.
bPDE4 was obtained from human U937 cells, rolipram binding pro-
tein was obtained from rat brain tissues and PDE3 was obtained from
human platelets.
aValues are shown as IC50 (mM) or percent inhibition at 1 mM for
PDE4 and 20 mM for PDE3 and are the means of at least two experi-
ments. RBA, rolipram binding assay.
As can be seen, a wide variety of substituents are toler-
ated at the 2-position of the furo[2,3-c]pyridine giving a
novel series of potent and selective PDE4 inhibitors.
The most potent compound with acceptable selectiv-
ity over binding at the rolipram site was found to
be 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic
acid (3,5-dichloro-1-oxopyridin-4-yl)amide 8a.
Having identified the 2-ethyl derivative 8a as a potent,
selective inhibitor of PDE4 we investigated the effect of
the 7-methoxy substituent. Removing the methyl group
to give the furo[2,3-c]pyridin-7(6H)-one analogue 9
resulted in a dramatic decrease in activity. However
replacing the 7-methoxy moiety with a 7-difluoro-
methoxy substituent to give compound 10 enhanced the
potency of this series of inhibitors (Table 2).
Removal of one chloro substituent from the parent
compound to give 11a resulted in a 10-fold drop in
activity against PDE4 as well as reducing the selectivity
for catalytic activity over binding to the rolipram site. A
similar effect was seen by replacing the chloro sub-
stituent with a methyl group as in compound 11b.
However the 3-methoxy analogue 11c had dramatically
reduced potency against PDE4. Incorporating a second
nitrogen in the ring as in the 5-cyanopyrimidin-4-yl
example 11d gave a compound with a very similar
activity and selectivity profile to the mono-substituted
pyridines 11a and 11b. Reasonably potent and selective
inhibition could be achieved after removing the pyri-
dine nitrogen as exemplified by 11e and 11f. However,
2-ethyl-7-methoxy-furo[2,3-c]pyridine-4-carboxylic acid
(3,5-dichloro-1-oxopyridin-4-yl)amide 8a remained our
most potent and selective compound in this series.
Table 2. 7-Substituted furo[2,3-c]pyridinesa
11
12
PDE4 IC50
RBA IC50
PDE4/RBA
PDE3
8a
9
10
0.014
22%
0.0037
0.084
61%
0.028
0.16
NA
0.13
32%
NT
NT
aValues are shown as IC50 (mM) or percent inhibition at 1 mM and are
the means of at least two experiments. RBA, rolipram binding assay.
Moving on to investigate the effect of replacing the 3,5-
dichloropyridyl-N-oxide moiety with other substituted
six-membered aromatic rings, a variety of aromatic
amines were coupled with 2-ethyl-7-methoxyfuro[2,3-
c]pyridine-4-carboxylic acid 4-nitrophenyl ester 7a in
the way previously described (Scheme 3). A series of
compounds 11 were thus prepared (Scheme 3) and tes-
ted in our in vitro assay (Table 3).
Given this high potency and selectivity, this compound
was selected for in vivo studies. Pharmacokinetic studies
in the guinea pig dosing at 3 mg/kg po showed a Cmax of
1411 ng/mL and an AUC of 4942 ng h/mL. The bio-
availability was found to be 54%. Using the same dos-
ing, the corresponding benzofuran analogue showed a
Cmax of 311 ng/mL and an AUC of 1394 ng h/mL. Thus
incorporation of the ring nitrogen has improved the
pharmacokinetics as predicted. The compound was then
evaluated in a guinea pig lung eosinophilia model.13
Administering po at 10 mg/kg, the compound showed
40% inhibition of lung eosinophilia (mean result of
three experiments).
Scheme 3. Reagents and conditions: (i) NaH or NaHMDS, DMF; (ii)
2-ethyl-7-methoxfuro[2,3-c]pyridine-4-carboxylic acid 4-nitropheyl
ester 7a.

512
G. M. Buckley et al. / Bioorg. Med. Chem. Lett. 12 (2002) 509–512
In summary, we have identified a series of novel
furo[2,3-c]pyridines as potent and selective PDE4 inhi-
bitors with a good pharmacokinetic profile. Significant
levels of oral activity were demonstrated in a functional
model of inflammation.
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