8-Methoxyquinolines as PDE4 inhibitors.

Article abstract of DOI:10.1016/S0960-894X(02)00224-X

The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4).

Full text of DOI:10.1016/S0960-894X(02)00224-X

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1617–1619
8-Methoxyquinolines as PDE4 Inhibitors
Motasim Billah,c George M. Buckley,a Nicola Cooper,a Hazel J. Dyke,a Robert Egan,c
Ashit Ganguly,c Lewis Gowers,a Alan F. Haughan,a Hannah J. Kendall,a
Christopher Lowe,a Michael Minnicozzi,c John G. Montana,a Janet Oxford,a
Joanna C. Peake,a C. Louise Picken,a John J. Piwinski,c Robert Naylor,b
Verity Sabin,a,* Neng-Yang Shihc and Julie B. H. Warnecka
aCelltech Group plc, Granta Park, Abington, Cambridge CB1 6GS, UK
bDept. of Pharmacology, University of Bradford, Bradford BD7 1DP, UK
cSchering-Plough Corporation, Galloping Hill Road, Kenilworth, NJ 07033-0530, USA
Received 8 March 2002; accepted 4 April 2002
Abstract—The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The
2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4). # 2002 Elsevier Science Ltd.
All rights reserved.
Inhibitors of PDE4 (a cAMP specific phosphodiesterase
found in inflammatory cells and airway smooth muscle)
have been investigated extensively as a potential treatment
for asthma.1 We have previously reported novel methoxy-
benzo-fused heterocycles (such as 7-methoxybenzofurans,2
7-methoxybenzimidazoles,3 8-methoxyquinolines3 and 7-
methoxyfuro-[2,3-c]-pyridines4) as PDE4 inhibitors. The
most efficacious of these compounds in vivo was the 8-
methoxyquinoline D4418.3 Because the in vitro and in vivo
profiles of D4418 were so promising, we next prepared a
series of 8-methoxyquinoline-5-carboxamides with a vari-
ety of substitutents at the 2-position. Our objective was to
improve in vitro potency, in vivo efficacy and plasma
exposure and half life.
The 8-methoxyquinolines 2a and 2b were prepared by
methylation of commercially available 8-hydroxy-
quinolines (Scheme 1).
2c was prepared by Skraup quinoline synthesis starting
with 2-methoxyaniline (Scheme 2).
o-Anisidine was reacted with ethyl 1,1,1-trifluoroacetate
in the presence of polyphosphoric acid to give a quino-
lone which was chlorinated at the 4-position with phos-
phorous pentachloride in phosphorous oxychloride. The
4-chloro substituent was removed by hydrogenation to
give 2d (Scheme 3).
2e was prepared from 2a using butyllithium followed by
iodomethane (Scheme 4).
The 8-methoxyquinolines 2a–2e were brominated para
to the methoxy group and then carbonylated to give
8-methoxyquinoline-5-carboxylic acids 3a–3e (Scheme 5).
3a–3e were activated as acid chlorides or p-nitrophenyl
esters and then reacted with the sodium salt of 4-amino-
3,5-dichloropyridine to give the 8-methoxyquinoline-5-
carboxamides 4a–4e (Scheme 6).
4b was reacted with methylmagnesium bromide to give
the 2-acetyl compound 4f which was itself reacted with
sodium borohydride to give 4g and with O-methyl-
hydroxylamine to give 4h (Scheme 7).
*Corresponding author. Tel.: +44-1223-896513; fax:+44-1223-
896400; e-mail: verity.sabin@celltechgroup.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00224-X

1618
M. Billah et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1617–1619
Scheme 1. Reagents and conditions: (i) MeI, NaOH, TBAI, THF,
H2O.
Scheme 6. Reagents and conditions: (i) C2Cl2O2, DMF, DCM or
p-nitrophenol, Et3N, DMAP, DCM; (ii) sodium salt of 4-amino-3,5-
dichloropyridine, DMF.
Scheme 2. Reagents and conditions: (i) H2SO4, I2, 2-ethyl acrolein.
Scheme 7. Reagents and conditions: (i) MeMgBr, THF; (ii) NaBH4,
EtOH; (iii) MeONH2, pyridine, toluene.
Scheme 3. Reagents and conditions: (i) EtO2CCH2COCF3, PPA;
(ii) PCl5, POCl3; (iii) H2, Pd/C.
poor ratio. However, replacing the methyl group of 4a
with trifluoromethyl (4d) improved activity against
PDE4. Of the two ethyl compounds 4c and 4e, the
2-isomer 4e was significantly more potent and had a bet-
ter ratio than the 3-isomer 4c. The 2-acetyl compound 4f
was less potent against PDE4 than D4418, and had a
similar ratio. Reduction of the acetyl group in 4f to give
the alcohol 4g improved activity against PDE4 and
maintained the ratio, while converting 4f to the methoxy
oxime 4h improved activity against both PDE4 and in
the RBAand was therefore detrimental to the ratio.
Scheme 4. Reagents and conditions: (i) BuLi, THF then MeI.
On the basis of its potency against PDE4 and selectivity
for the catalytic site over the rolipram binding site, 4d
was selected for evaluation in guinea pig pharmacoki-
netic studies7 and in a guinea pig lung eosinophilia
study.8 Pharmacokinetic studies in the guinea pig (Fig.
1), dosing orally at 5 mg/kg, showed 4d to have a Cmax
of 380 ng/mL, an AUC of 1174 ng h/mL and an oral
bioavailability of 78%.
Scheme 5. Reagents and conditions: (i) Br2, MeOH; (ii) CO,
PdCl2(PPh3)2, Et3N, THF or DMF, H2O.
The 8-methoxyquinoline-5-carboxamides 4a–4h were
screened in vitro against PDE4 and PDE3, and in a
rolipram binding assay (RBA) (Table 1).
In a guinea pig lung eosinophilia model, 4d caused sig-
nificant levels of inhibition of eosinophil influx when
administered orally at 10 and 3 mg/kg (Fig. 2).
4a was 2-fold more potent against PDE4 than D4418.
Incorporating nitrile at the 2-position (4b) not only
decreased activity against PDE4 but also increased
activity at the rolipram binding site, leading to a very
4d was assessed for emetic side effects in a ferret emesis
model.9 No emesis was observed when the compound
was dosed orally at 6 mg/kg to a group of four animals.

M. Billah et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1617–1619
Table 1. 2-Substituted quinoline-5-carboxamidesa
1619
5
6
R
R1
PDE4 IC50
RBAIC 50
PDE 4:RBAPDE 3 (%)
D4418
4a
4b
4c
4d
4e
4f
4g
H
CH3
CN
H
CF3
H
H
0.17
0.088
0.70
0.21
0.051
0.043
0.44
0.18
0.21
0.53
0.32
1.19
16.28
1.31
0.66
0.57
0.29
0.22
1.5
10
0.074
0.043
0.16
0.077
0.0753
1.5
21
38
12
15
35
27
30
22
H
CH2CH3
H
H
H
H
H
CH2CH3
C(O)CH3
C(OH)CH3
C(NOCH3)CH3
0.79
0.14
4h
aValues are shown as IC50 (mM) or per cent inhibition at 20 mM and are the means of at least two experiments. RBA, rolipram binding assay. PDE4
was obtained from human U937 cells, rolipram binding protein was obtained from rat brain tissues, and PDE3 was obtained from human platelets.
In conclusion, 4d is a novel, potent and selective inhi-
bitor of PDE4. Compared with D4418, it had an
improved plasma half life in vivo when dosed orally to
guinea pigs, and significantly improved activity in a
guinea pig lung eosinophilia model. Further studies on
compounds in this series will be reported in due course.
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Figure 2. Inhibition of guinea pig lung eosinophilia by oral dosing of
4d at 1, 3 and 10 mg/kg.