Synthesis and profile of SCH351591, a novel PDE4 inhibitor

Article abstract of DOI:10.1016/S0960-894X(02)00225-1

The syntheses and pharmacological profiles of some 2-trifluoromethyl-8-methoxyquinoline-5-carboxamides are described. SCH351591 is a potent selective inhibitor of phosphodiesterase type 4 (PDE4).

Full text of DOI:10.1016/S0960-894X(02)00225-1

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1621–1623
Synthesis and Profile of SCH351591, a Novel PDE4 Inhibitor
Motasim Billah,c Nicola Cooper,a Francis Cuss,c Richard J. Davenport,a Hazel J. Dyke,a
Robert Egan,c Ashit Ganguly,c Lewis Gowers,a Duncan R. Hannah,a Alan F. Haughan,a
Hannah J. Kendall,a Christopher Lowe,a Michael Minnicozzi,c John G. Montana,a
Robert Naylor,b Janet Oxford,a Joanna C. Peake,a John J. Piwinski,c Karen A. Runcie,a
Verity Sabin,a,* Andrew Sharpe,a Neng-Yang Shihc and Julie B. H. Warnecka
aCelltech Group plc, Granta Park, Abington, Cambridge CB1 6GS, UK
bDepartment 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 syntheses and pharmacological profiles of some 2-trifluoromethyl-8-methoxyquinoline-5-carboxamides are described.
SCH351591 is a potent selective inhibitor of phosphodiesterase type 4 (PDE4). # 2002 Elsevier Science Ltd. All rights reserved.
PDE4 inhibitors are a class of compounds that have
been extensively investigated as a treatment for asthma
and other inflammatory disorders.1 We have recently
reported a novel series of 8-methoxyquinoline-5-carbox-
amide PDE4 inhibitors which had good selectivity for
PDE4 and an acceptable therapeutic ratio for binding at
the catalytic site over the rolipram binding site.2 Of this
series, one of the most potent compounds in vitro was the
2-trifluoromethyl quinoline SCH365351. SCH365351
was active in a guinea pig lung eosinophilia model3
when dosed at 10 and 3 mpk and also had good plasma
exposure in guinea pigs.
Figure 1. PK profile of SCH365351 and the major metabolite in rats.
levels of metabolite were higher than those of the parent
compound.
The metabolite was identified as the pyridine N-oxide, a
discovery which prompted us to investigate the profile
of this compound and the SAR around other pyridine
N-oxides of that type.
However, a major metabolite was observed in a rat PK
study on SCH365351 (Fig. 1). At time points >3 h, the
SCH365351 was dissolved in chloroform and treated
with peracetic acid to give the N-oxide 3a (Scheme 1).
8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid
was activated by conversion either to the acid chloride
or to the p-nitrophenyl ester and then reacted with the
*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)00225-1

1622
M. Billah et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1621–1623
sodium salts of various substituted 4-amino pyridines to
give amides such as 2b–2d (Scheme 2).
The activities of the N-oxides 3a–3d against PDE4 were
similar to or improved over those of the parent pyri-
dines SCH365351 and 2b–2d. The PDE4:RBA ratios
were improved except in the case of 3d. Both the
monochloro and dimethyl compounds 3b and 3c were
significantly less active against PDE4 than 3a; the
difluoro compound 3d, though of similar activity to 3a
against PDE4, had a much poorer ratio. The dichloro-
pyridine-N-oxide 3a was therefore selected for further
studies and given the number SCH351591.
These were oxidised to the N-oxides 3b–3d using per-
acetic acid as described above. 2b–2d and 3a–3d were
screened in vitro against PDE4 and in a rolipram bind-
ing assay (RBA) (Table 1).
SCH351591 was screened against other PDEisozymes
and was found to be selective for PDE4 over PDE1, 2,
3, 5 and 7 (Table 2).
Pharmacokinetic studies6 in the rat (Fig. 2), dosing
orally at 3 mg/kg, showed SCH351591 to have a Cmax of
3058 ng/mL and an AUC0-t of 50503 ng h/mL, a con-
siderable improvement over SCH365351 (Cmax
1008 ng/mL, AUC0-t=6860 ng h/mL).
=
Scheme 1. Reagents and conditions: (i) peracetic acid (36–40% in
acetic acid), 50 ꢀC, 7 days, CHCl3.
The guinea pig PK profile (Fig. 3), was also greatly
improved over SCH365351. (Cmax of 1393 ng/mL and
an AUC0-t of 15757 ng h/mL when dosed orally at 3 mg/
kg compared with Cmax=380 ng/mL and AUC0-t
1174 ng h/mL for SCH365351.)
=
When administered orally in a guinea pig lung eosino-
philia model,7 SCH351591 caused significant levels of
inhibition of eosinophil influx at 10, 3 and 1 mg/kg
(Fig. 4).
SCH351591 was assessed for emetic side effects in a
ferret emesis model.8 No emesis was observed when the
Scheme 2. Reagents and conditions: (i) C2Cl2O2, DMF, DCM or
p-nitrophenol, Et3N, DMAP, DCM; (ii) sodium salt of appropriate
amino pyridine, DMF.
Table 1. 2-Trifluoromethylquinoline-5-carboxamidesa
4
5
R
R1 PDE4 IC50 RBA IC50 PDE4:RBA
SCH365351
Cl Cl
Cl
Me Me
0.051
1.12
0.12
0.035
0.06
0.24
0.15
0.07
0.077
0.11
0.058
0.038
0.15
0.37
0.38
0.06
0.66
10
2.1
0.94
0.40
0.65
0.39
1.17
2b
2c
2d
H
F
F
3a (SCH351591) Cl Cl
3b
3c
3d
Cl H
Me Me
F
F
aValues are shown as IC50 (mM) and are the means of at least two
experiments. RBA, rolipram binding assay. PDE4 was obtained from
human U937 cells and rolipram binding protein was obtained from rat
brain tissues.
Figure 2. PK profile of SCH351591 in rats dosed orally at 3 mg/kg
(n=3).
Table 2. In vitro profile of SCH351591a
PDE4
PDE1
PDE2
PDE3
PDE5
PDE7
0.06
15%
0%
31%
5%
10%
aValues are shown as IC50 (mM) or percent inhibition at 10 mM and are
the means of at least two experiments. PDE1 was recombinant
enzyme, PDE2, 3 and 5 were obtained from human platelets, PDE7
was obtained from a human T-lymphocyte cell line.
Figure 3. PK profile of SCH351591 in guinea pigs dosed orally at
3 mg/kg (n=3).

M. Billah et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1621–1623
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Figure 4. Inhibition of guinea pig lung eosinophilia by oral dosing of
SCH351591.
compound was dosed orally to a group of four animals
at 5 mg/kg each, despite appreciable plasma levels
(Cmax=3500 ng/mL, AUC0-t=26700 ng h/mL) at this
dose.
In summary, SCH351591 is a potent selective inhibitor
of PDE4 with an excellent PK profile and significant
activity in an in vivo model at doses which showed no
emetic side effects. It was therefore selected for further
studies, and details on the outcome of these will be dis-
closed in subsequent publications.
8. Costall, B.; Domeney, A. M.; Naylor, R. J.; Tattersall,
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