Alkyl-bridged substituted 8-arylquinolines as highly potent PDE IV inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.03.105

Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-454560. The pharmacokinetic profile of the b

Full text of DOI:10.1016/j.bmcl.2009.03.105

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5266–5269
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Alkyl-bridged substituted 8-arylquinolines as highly potent PDE IV inhibitors
*
Patrick Lacombe , Nathalie Chauret, David Claveau, Stephen Day, Denis Deschênes, Daniel Dubé,
Michel Gallant, Yves Girard, Zheng Huang, France Laliberté, Jean-Francois Lévesque, Susana Liu,
Dwight Macdonald, Joseph A. Mancini, Paul Masson, Donald W. Nicholson, Deborah A. Nicoll-Griffith,
Myriam Salem, Angela Styhler, Robert N. Young
Merck Frosst Center for Therapeutic Research, PO Box 1005, Pointe Claire—Dorval, Québec, Canada H9R 4P8
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of
type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-
454560. The pharmacokinetic profile of the best analogs and the in vivo efficacy in an ovalbumin-induced
bronchoconstriction assay in conscious guinea pigs are reported.
Received 6 February 2009
Revised 19 March 2009
Accepted 23 March 2009
Available online 26 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
PDE 4
COPD
Asthma
Bronchoconstriction
The 50-cyclic nucleotide phosphodiesterases (PDEs) are a large
family of bimetallic hydrolases responsible for the hydrolysis and
consequent deactivation of cAMP and cGMP.1 Of the eleven
families, the cAMP-specific PDE4s (encoded by four genes) are par-
ticularly abundant in inflammatory cells, immune cells and in
airway smooth muscle cells,2 where inhibition of PDE4s blocks cell
trafficking, cell proliferation, and modulates the production of
among the four PDE4 isoforms,8 as well as restricting the com-
pound tissue distribution.9
We previously disclosed a successful approach which led to the
identification of our first clinical candidate L-454560 (1) (Fig. 1).10
Although the compound was well tolerated, its inhibition of cyto-
chrome P450 2C9 (IC50 of 0.2 lM) and potential liability of olefin-
isomerisation prompted us to initiate a back-up program. Part of
our efforts toward overcoming these two liabilities was recently
published.11 In extension of this work, we would like to report a
series of alkyl-linked 8-arylquinolines as highly potent human
PDE4 inhibitors.
Our initial SAR efforts focused on the evaluation of a series of
ketones as previous studies suggested that a hydrogen bond accep-
tor could exhibit greater potency.12 The relative intrinsic potency
of these analogs is expressed as an average of the potency for three
inflammatory mediators and cytokines, including LTB4, TNF-
a, IL-
2, IFN
c
, as well as reactive oxygen species.3 In animal models,
PDE4 inhibitors are generally anti-inflammatory and bronchodila-
tory. A number of them, including roflumilast, cilomilast and
rolipram, were evaluated in humans and they have shown promis-
ing clinical efficacy for asthma, chronic obstructive pulmonary
disease (COPD), atopic dermatitis and rheumatoid arthritis.4
Among them, roflumilast has shown a significant improvement
in FEV1 after 24 week treatment in COPD patients.5
Despite the promising clinical efficacy of PDE4 inhibitors, the
major impediment for their further clinical development has been
their mechanism-related adverse effects including nausea, emesis,
and gastrointestinal adverse events.6 In order to further improve
the therapeutic window of efficacy over emesis and GI adverse
events, several approaches have been attempted, including the
designing of a highly emetic photoaffinity probe to elucidate the
molecular targets of emesis versus efficacy,7 selective targeting
O
O
S
N
O
N
N
L-454560 (1)
O
S
O
* Corresponding author. Tel.: +1 514 428 8686.
E-mail address: patrick_lacombe@merck.com (P. Lacombe).
Figure 1. Clinical candidate L-454560.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.105

P. Lacombe et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5266–5269
5267
Table 1
for compound 10 translated to a 36-fold improvement in the ther-
apeutic index over L-454560. Unfortunately, the overall pharmaco-
kinetic profile in rats for these inhibitors showed no improvement
over the ketone derivatives discussed in Table 1. We then decided
to block the benzylic position by introducing a fluorine atom. The
pharmacokinetic profiles of these newly prepared fluoro analogs
were then systematically evaluated (Table 3). Alcohol 12 showed
a significant improvement over the non-fluorinated analog 9,
decreasing its clearance from 50 ml/min/kg to 17 ml/min/kg. Fur-
thermore, the introduction of the benzylic fluorine atom improved
the bioavailability from 21% to 84%.
Biological data for ketones 2–6
S
O
O
O
R
N
S
O
O
Compd
R
PDE4-ABDQT
IC50 (nM)
HWB
IC50
CYP2C9
IC50 (lM)
a
b
a
(lM)
Having solved the pharmacokinetic issue in rats, maintained the
potency over PDE 4 and kept the affinity for CYP 2C9 low (Table 3),
we decided to concentrate our efforts on finding more potent ana-
logs. Introducing a methylsulfonyl group, exemplified by com-
pound 13, did not translate into a significantly more potent
analog, while incorporating a phosphonyl group led to a compound
with very high clearance (entry 14). Increasing the lipophilicity as
in the biscyclopropyl 15 gave a compound with improved HWB po-
tency. The same modification could also be applied in the sulfone
series and led to the potent derivative 16. In fact, once being re-
solved by chiral HPLC,16 compounds such as 18 and 20 were found
to be over 10 times more potent than L-454560 (1) in the HWB
2
3
4
5
6
Me
4-F-Ph
3-Pyridinyl
t-Bu
Dimethylcarbinol
1.7
1.4
0.9
1.4
1.4
0.3 ( 0.1)
0.8 ( 0.5)
0.3 ( 0.1)
0.3 ( 0.1)
0.4 ( 0.2)
0.6
0.2
0.2
0.7
3.6
a
Values are means of at least two experiments.
Values are means of three experiments, standard deviation is given in
b
parentheses.
human PDE4 isoforms (A, B, D).13 The compounds described in this
Letter displayed little or no isozyme specificity. Also, their cellular
based functional efficacy at blocking the LPS-induced TNF-
a re-
(IC50 = 0.2 lM).
lease in human whole blood (HWB),14 and their inhibition of the
Compounds 18 and 20 were then further profiled (Table 4). The
observed increase in HWB potency did translated similarly in our
in vivo model.17 Compared to L-454560 (1), which showed a 53%
inhibition of ovalbumin-induced bronchoconstriction in conscious
guinea pigs at 0.03 mg/kg, compounds 18 an 20 showed 85% and
73% inhibition when dosed interperitoneally (ip) at 0.01 mg/kg,
respectively. Evaluation of their propensity to cause emesis was
then established by dosing in squirrel monkeys (SqM). For the
bis-cyclopropane analog 18, emesis was observed at a plasma con-
Cytochrome P450 2C9,15 are summarized in Table 1.
Varying the substitution of the ketones from a methyl to a 4-
fluorophenyl, 3-pyridinyl or a tert-butyl (compounds 2–5) did
not affect the activity in the enzyme assay nor in the whole blood
assay. However, adding a tertiary alcohol, as exemplified by com-
pound 6, decreased the CYP 2C9 affinity. Furthermore, when we
evaluated the pharmacokinetic profile of these new analogs (2–
6), we found a significant amount of
a-hydroxylated ketone
metabolite circulating for all of them, except for compound 6. That
observation led us to postulate that the metabolite arises from oxi-
dation of the enol form of the molecule which is prevented by the
internal hydrogen bond present for the hydroxyketone 6. Follow-
ing that hypothesis, we replaced the ketone functionality by other
hydrogen bond acceptor substituents described in Table 2.
By introducing polar functionalities such as an alcohol (com-
pounds 7–9), sulfone 10 or phosphonate 11, we were able to gain
potency in the HWB assay while decreasing the inhibitory activity
for CYP 2C9. For example, the decreased CYP 2C9 activity observed
centration of 0.2 lM or 100-fold over its IC50 in the SqM whole
blood assay (Table 4). The therapeutic window of potency versus
emesis was even greater for compound 20 where emesis was dis-
played at a concentration of 1.9 lM. This 1900-fold window com-
pared favorably over the 380-fold therapeutic index observed for L-
454560 (1).
All the compounds described18 in this Letter were prepared
from the previously disclosed 8-bromo-6-[1-methyl-1-(methylsul-
fonyl)ethyl]quinoline (21)10b following the synthetic approach de-
scribed in Scheme 1. Suzuki coupling of arylbromide 21 with 3-
Table 2
Biological data for derivatives 7–11
S
R
O
O
N
S
O
O
Compd
R
PDE4-ABDQT
IC50 (nM)
HWB
IC50
CYP2C9
IC50 (lM)
Rat PKc
Fd, Cle
a
b
a
(l
M)
7
8
9
10
11
CH2OH
1.5
0.3
0.7
0.9
1.3
0.21 ( 0.04)
0.09 ( 0.06)
0.10 ( 0.09)
0.19 ( 0.09)
0.03 ( 0.02)
3.6
1.5
6.4
6.9
11.4
9, 51
—
21, 50
1, 76
3, 48
t-Butylcarbinol
Dimethylcarbinol
SO2Me
PO(OMe)2
a
Values are means of at least two experiments.
Values are means of three experiments, standard deviation is given in parentheses.
Dosed as 60% PEG 200/water solution.
Bioavailability (F) expressed in percentage.
Clearance is expressed in ml/min/kg and calculated using the following formula: Cl = (Dose IV)(1E6)/(Total AUC IV)(Mol. weight).
b
c
d
e

5268
P. Lacombe et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5266–5269
Table 3
Biological data for derivatives 12–20
S
O
O
N
R
F
12-20
S
O
O
Compd
R
PDE4-ABDQT
IC50 (nM)
HWB
IC50
CYP2C9
IC50 (lM)
Rat PKc
Fd, Cle
a
b
a
(lM)
1
12
13
14
15
16
17
—
1.0
0.8
0.6
0.4
0.4
0.2
0.4
0.2 ( 0.1)
0.2 ( 0.2)
0.1 ( 0.1)
0.1 ( 0.09)
0.04 ( 0.02)
0.08 ( 0.07)
0.02
( 0.05)
0.006
( 0.003)
0.09
( 0.06)
0.2
4.6
4.5
—
2.8
3.8
2.1
100, 7
84, 17
53, 9
51,177
99, 8
—
Dimethylcarbinol
SO2Me
PO(OMe)2
(c-Pr)2carbinol
SO2(c-Pr)
(c-Pr)2carbinol
Enantio A
(c-Pr)2carbinol
Enantio B
SO2(c-Pr)
69, 11
18
19
20
0.2
0.2
0.2
3.8
3.7
3.9
99, 38
36, 9
99, 3
Enantio A
SO2(c-Pr)
0.015
Enantio B
( 0.002)
a
Values are means of at least two experiments.
Values are means of three experiments, standard deviation is given in parentheses.
Dosed as 60% PEG 200/water solution.
Bioavailability (F) expressed in percentage.
Clearance is expressed in ml/min/kg and calculated using the following formula: Cl = (Dose IV)(1E6)/(Total AUC IV)(Mol. weight).
b
c
d
e
Table 4
In vivo data for derivatives 18 and 20
S
S
F
O
O
O
O
O
O
N
N
S
F
OH
18
20
S
S
O
O
O
O
SqM PKb
Cmax M) @ dose (mpk)
Ratioc Cmax/IC50
Guinea pigd % @
lg/kg
a
Compd
SqM WB IC50
(
lM)
(
l
1
18
20
0.01
0.001
0.001
3.8 @ 10
0.1 @ 0.4
1.9 @ 2
380
100
1900
53 @ 30
85 @ 10
73 @ 10
a
Values are means of two experiments.
Squirrel monkey plasma concentration at which emesis was observed in at least two animals when dose as a 60% PEG200/water solution.
Ratio of SqM plasma concentration at which emesis was observed over SqM whole blood IC50
Percentage of inhibition of ovalbumin-induced bronchoconstriction following ip injection.
b
c
.
d
(hydroxymethyl)benzeneboronic acid afforded the desired biaryl
scaffold 22. The latter was converted to a common intermediate
23 by treatment with HBr 48% in acetic acid. Prior to being trans-
formed into their fluorinated analogs (13, 14, and 16) by treatment
with sodium tert-butoxide and FN(SO2Ph)2 in THF, the benzyl bro-
mide 23 was converted into derivatives (2–6, 10, and 11) by alkyl-
ation with the proper benzylic groups (24–28) whose syntheses
are described in Scheme 2.
Displacement of 4-methylthiobenzyl chloride either with sulfur
followed by cyclopropyl magnesium bromide, sodium methane-
sulfinate or trimethyl phosphite under Arbuzov conditions led to
the corresponding thioether which were all oxidized to the sulfone
(24–26) using oxone as reagent. Alternatively, compounds 27 and
28 were prepared by a palladium mediated coupling of 4-meth-
ylthiobromobenzene with an appropriate methylketone followed
by oxone oxidation.
SO2Me
Br
SO2Me
b
SO2Me
a
N
N
N
Br
OH
23
21
22
EWG
c
S
O
O
SO2Me
SO2Me
d
N
N
EWG
EWG
F
13, 14, 16
2-6, 10,11
S
S
O
O
O
O
The alkylation of benzyl bromide 23 described earlier could also
be performed with ethyl 4-methylthiophenylacetate to afford the
substituted phenylacetate 29. The latter was then either converted
Scheme 1. Reagents and conditions: (a) 3-(hydroxymethyl)benzeneboronic acid,
Pd(PPh3)4, Na2CO3 (2 M in H2O), n-PrOH, 80 °C (b) HBr 48%, AcOH (c) t-BuOK, THF/
DMF (1:1). (d) t-BuOK, FN(SO2Ph)2, THF/DMF (1:1).

P. Lacombe et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5266–5269
5269
References and notes
a,b,c
S
O
O
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S
S
24
O
O
O
O
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(b) Soderling, S. H.; Beavo, J. A. Curr. Opin. Cell Biol. 2000, 12, 174.
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Cl
S
d, c
e, c
O
O
O
S
25
P
O
O
S
O
O
26
O
OH
f, c
OH
O
S
Br
O
O
27
28
O
S
f, c
O
S
O
O
Scheme 2. Reagents and conditions: (a) S8, NaOH, TBAI, PEG400/benzene, 80 °C (b)
c-PrMgCl, THF (c) oxone, THF/MeOH/H2O (2:1:1) (d) MeSO2Na, DMF. (e) P(OMe)3,
140 °C (f) Pd2(dba)3, Xantphos, t-BuONa, THF, 65 °C.
7. Macdonald, D.; Perrier, H.; Liu, S.; Laliberté, F.; Rasori, R.; Robichaud, A.;
Masson, P.; Huang, Z. J. Med. Chem. 2000, 43, 3820.
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Yamada, T. J. Pharmacol. Exp. Ther. 2001, 298, 1142; (b) Bureau, Y.; Handa, M.;
Zhu, Y.; Laliberté, F.; Moore, C. S.; Liu, S.; Huang, Z.; Macdonald, D.; Xu, D. G.;
Robertson, G. S. Neuropharmacology 2006, 51, 974.
SO2Me
SO2Me
N
a
10. (a) Huang, Z.; Dias, R.; Jones, T.; Liu, S.; Styhler, A.; Claveau, D.; Out, F.; Ng, K.;
Laliberté, F.; Zhang, L.; Goetghebeur, P.; Abraham, W. M.; Macdonald, D.; Dubé,
D.; Gallant, M.; Lacombe, P.; Girard, Y.; Young, R. N.; Turner, M. J.; Nicholson, D.
W.; Mancini, J. A. Biochem. Pharmacol. 2007, 73, 1971; (b) Macdonald, D.;
Mastracchio, A.; Perrier, H.; Dubé, D.; Gallant, M.; Lacombe, P.; Deschênes, D.;
Roy, B.; Scheigetz, J.; Bateman, K.; Li, C.; Trimble, L. A.; Day, S.; Chauret, N.;
Nicoll-Griffith, D. A.; Silva, J. M.; Huang, Z.; Laliberté, F.; Liu, S.; Ethier, D.; Pon,
D.; Muise, E.; Boulet, L.; Chan, C. C.; Styhler, A.; Charleson, S.; Mancini, J.;
Masson, P.; Claveau, D.; Nicholson, DW.; Turner, M. J.; Young, R. N.; Girard, Y.
Bioorg. Med. Chem. Lett. 2005, 15, 5241.
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Z.; Lacombe, P.; Laliberté, F.; Lévesque, J-F.; Liu, S.; Macdonald, D.; Mancini, J.;
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1407.
N
O
R
O
O
X
X
2-4
S
S
29
O
O
O
O
a
X: H, F.
SO2Me
N
R
R
OH
12. Lacombe, P.; Deschênes, D.; Dubé, D.; Dubé, L.; Gallant, M.; Macdonald, D.;
Mastracchio, A.; Perrier, H.; Charleson, S.; Huang, Z.; Laliberté, F.; Liu, S.;
Mancini, J. A.; Masson, P.; Salem, M.; Styhler, A.; Girard, Y. Bioorg. Med. Chem.
Lett. 2006, 16, 2608.
X
9, 12, 15
S
O
O
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Biochemistry 2000, 39, 6449; (b) Liu, S.; Laliberté, F.; Bobechko, B.; Lario, P.;
Gorseth, E.; Van Hamme, J. Biochemistry 2001, 40, 10179.
Scheme 3. Reagents: (a) RMgCl, THF.
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Pharmacol. 1999, 126, 979.
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Acad. Sci. 2000, 919, 26.
into the fluorinated analogs using conditions described earlier and/
or the corresponding ketone (2–4) and alcohol (9, 12, and 15) by
treatment with an appropriate Grignard reagent (Scheme 3).
In conclusion, we have identified two potent and selective PDE4
inhibitors, compounds 18 and 20, which have improved potency
and metabolic profile across the species in comparison to the clin-
ical candidate L-454560 1. In addition, these inhibitors are devoid
of the metabolically unstable olefin and have little affinity against
CYP 2C9. Finally, their excellent pharmacokinetic properties re-
sulted in compounds with improved in vivo functional efficacy as
measured in our guinea pig model of bronchoconstriction.
16. Separation of the two enantiomers 17 and 18 was performed by chiral HPLC
(Chiralpak AD 5 ꢀ 50 cm, 20
ethanol, (rt = 30 and 43 min.). Separation of the two enantiomers 19 and 20
, 55 ml/min, 30%
l, 70 ml/min, 60% hexanes, 20% iso-propanol, 20%
was performed by chiral HPLC (Chiralpak AD 5 ꢀ 50 cm, 20
l
hexanes, 30% iso-propanol, 30% ethanol, 10% methanol (rt = 63 and 81 min.).
17. (a) Jones, T. R.; McAuliffe, M.; McFarlane, C. S.; Piechuta, H.; Macdonald, D.;
Rodger, I. W. Can. J. Physiol. Pharmacol. 1998, 76, 210; (b) Danahay, H.; Broadley,
K. J. Clin. Exp. Allergy 1998 Apr, 28, 513; (c) Abraham, W. M.; Ahmed, A.; Cortes,
A.; Sielczak, M. W.; Hinz, W.; Bouska, J.; Lanni, C.; Bell, R. L. Eur. J. Pharmacol.
1992, 217, 119.
18. More detailed procedures can be found in WO2003002118.