Nitrogen-bridged substituted 8-arylquinolines as potent PDE IV inhibitors

Article abstract of DOI:10.1016/j.bmcl.2006.02.043

Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing nitrogen-linked side chain were identified as potent inhibitors based on the SAR described herein. The pharmacokinetic profile of the best analog and t

Full text of DOI:10.1016/j.bmcl.2006.02.043

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2608–2612
Nitrogen-bridged substituted 8-arylquinolines as potent
PDE IV inhibitors
*
´
´
Patrick Lacombe, Denis Descheˆnes, Daniel Dube, Laurence Dube, Michel Gallant,
`
´
Dwight Macdonald, Antony Mastracchio, Helene Perrier, Stella Charleson, Zheng Huang,
´
France Laliberte, Susana Liu, Joseph A. Mancini, Paul Masson, Myriam Salem,
Angela Styhler and Yves Girard
Merck Frosst Center for Therapeutic Research, PO Box 1005, Pointe Claire—Dorval, Que., Canada H9R 4P8
Received 6 January 2006; revised 14 February 2006; accepted 15 February 2006
Available online 3 March 2006
Abstract—Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing nitrogen-
linked side chain were identified as potent inhibitors based on the SAR described herein. The pharmacokinetic profile of the best
analog and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Type 4 c-AMP specific phosphodiesterase (PDE IV) is
S
O
O
an enzyme responsible for the hydrolysis of the 2nd
messenger c-AMP in many cell types.1 Inhibition of
this enzyme can significantly increase the intracellular
c-AMP concentration, leading to major alterations in
cell biochemistry and function.1c For example, some
inflammatory processes and antigen-induced broncho-
spasm can be attenuated using a PDE IV inhibitor.2
Because inflammation and bronchoconstriction are
major factors of respiratory diseases such as asthma
and COPD (chronic obstructive pulmonary disease),
the inhibition of PDE IV enzyme represents a promis-
ing therapeutic target. One of the major issues associ-
ated with the development of PDE IV inhibitors,
however, has been their propensity to induce emesis.
This observation has been reported on several proto-
typical compounds.3,4
N
S
1
O
N
N
O
O
In an effort to expand the SAR in this series of 8-aryl-
quinolines, we explored the possibility of introducing
heteroatoms to replace the photolytically unstable ole-
finic linker. Of all the potential replacements investigat-
ed, including ethers, thioethers, sulfones, and
sulfonamides, the analogs bearing amine and amide
linkers were found to be the most promising replace-
ments for the double bond found in compound 1.
We recently disclosed a new class of substituted 8-aryl-
quinolines as potent and well-tolerated (emesis) PDE
IV inhibitor5 exemplified by compound 1.
Our initial SAR efforts focused on the evaluation of the
amide tether. For that purpose, a series of compounds
were prepared following the synthetic approach de-
scribed in Scheme 1. Suzuki coupling of aryl bromide
2 and 3-carboxybenzeneboronic acid or 3-aminobenzen-
eboronic acid afforded the desired intermediates 3 and 4,
respectively. The latter was converted to the correspond-
ing amide analogs (5–10) using HATU as the coupling
reagent. The specific affinities of these derivatives for
the four isoforms of the human PDE IV enzyme6 were
Keywords: PDE4; TNF-a; c-AMP; Asthma; COPD.
*
Corresponding author. Tel.: +1 514 428 8686; e-mail:
patrick_lacombe@merck.com
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.02.043

P. Lacombe et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2608–2612
2609
measured. Their respective ability to block the release of
TNF-a through inhibition of PDE IV in a LPS stimu-
lated human whole blood assay (HWB) was also evalu-
ated.7 The results are summarized in Tables 1 and 2.
SO2Me
SO2Me
c
SO2Me
a
N
N
N
Br
H
N
R
2
OH
Both amide linkers (5,6) are equipotent in the enzyme
assay but differ substantially (10-fold) in the human
whole blood assay. Because the activity of amide 6 is less
shifted in the presence of plasma proteins, it was selected
as the linker of choice for further SAR. As exemplified
by aryl amide 8 and primary amide 7, substitution is re-
quired to obtain intrinsic potency on the PDE IV en-
zymes. Moreover, in order to achieve potency in the
HWB assay, polar substituents in the para position are
required (compounds 6, 9, and 10).
3
b
6-10
O
O
SO2Me
SO2Me
d
N
N
O
R
N
NH2
H
5
4
Scheme 1. Reagents and conditions: (a) 3-carboxybenzeneboronic
acid, Pd(PPh3)4, Na2CO3, n-PrOH, 80 ꢁC; (b) 3-aminobenzeneboronic
acid, Pd(PPh ) , Na CO , n-PrOH, 80 ꢁC; (c) amine, HATU, Hunig’s
¨
Having successfully replaced the olefinic moiety of com-
pound 1, we then evaluated the pharmacokinetic profile
3 4
2
3
base, DMF; (d) carboxylic acid, HATU, Hunig’s base, DMF.
¨
Table 1. Biological data for amide derivatives 5 and 6
S
O
R
O
N
S
O
O
GST-PDE IVQTIC50 (nM)
HWB IC50 (lM)
a
b
Compound
R
A
B
C
D
O
5
6
1.7
1.2
10.6
2.3
1 ( 1)
N
H
H
N
3.5
0.5
26
2.8
0.14 ( 0.06)
O
a Values are means of two experiments.
b Values are means of three experiments, standard deviation is given in parentheses.
Table 2. Biological data for amide derivatives 7–10
S
O
O
O
R
N
H
N
a
b
Compound
R
GST-PDE IVQT IC50 (nM)
HWB IC50
(lM)
A
B
C
D
7
8
H
Ph
78
16
40
490
97
74
10
—
5.9
7 ( 3)
9
3.1
0.9
0.4
17
3.0
0.2 ( 0.1)
N
Cl
10
0.6
5.5
0.7
0.09 ( 0.03)
N
Cl
a Values are means of two experiments.
b Values are means of three experiments, standard deviation is given in parentheses.

2610
P. Lacombe et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2608–2612
of these new compounds. We observed that most of
these amides were poorly absorbed after oral dosing
and were readily metabolized in rats to the inactive car-
boxylic acid 3.
prepared. These analogs were synthesized via the Suzuki
coupling of aryl bromide 2 or 2a and 3-formylbenzeneb-
oronic acid, followed by their reductive amination with
4-methylthioaniline to give amine 12. This amine could
then be converted into either an amide, urea or carba-
mate. Finally, oxidation using oxone produced the
desired sulfones 14a–19a (Table 3).
In an attempt to overcome this metabolic instability, a
series of tertiary amines and amides (Table 3) were
Table 3. Biological data for derivatives 14a–19a
N
N
R
N
S
O
O
a
b
Compound
R
GST-PDE IVQT IC50 (nM)
HWB IC50
(lM)
A
B
C
D
14a
15a
16a
17a
18a
19a
1.0
0.1
9.5
0.5
1.8 ( 0.6)
F
O
O
0.2
0.3
0.1
0.1
0.3
0.1
0.1
0.1
0.03
0.3
1.0
0.9
1.7
0.05
4.2
0.3
0.1
0.1
0.1
0.3
0.08 ( 0.03)
0.03 ( 0.005)
0.14 ( 0.14)
0.04 ( 0.04)
0.08 ( 0.03)
N
O
O
N
H
O
N
H
O
O
a Values are means of two experiments.
b Values are means of three experiments, standard deviation is given in parentheses.
Table 4. Biological data for derivatives 20–23
S
O
O
O
N
NH
N
R1 R2
S
O
O
a
b
Compound
R1
R2
GST-PDE IVQT IC50 (nM)
HWB IC50
(lM)
A
B
C
D
20
21
22
23
H
Cl
F
H
0.1
15
0.6
1.8
0.1
4.4
0.3
0.7
1.7
70
6.4
25
0.1
10
0.8
1.9
0.1 ( 0.1)
4 ( 1)
H
H
Me
0.05 ( 0.02)
0.4 ( 0.4)
H
a Values are means of two experiments.
b Values are means of three experiments, standard deviation is given in parentheses.

P. Lacombe et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2608–2612
2611
Tertiary amines as exemplified by 14a exhibited good
intrinsic potency but were found to be highly shifted
in the HWB assay. Whole blood activity was regained
by reintroducing the carbonyl group outside the tether
(14a vs 15a). Carbamate (19a) and ureas (17a, 18a) were
also found to exhibit acceptable whole blood potencies.
Unfortunately, as it was the case for the previous amide
series, these series of compounds were metabolically
unstable. Indeed, oxidative cleavage occurred in vivo
leading to carboxylic acid 3a as the main circulating
metabolite observed in rat plasma following oral dosing.
For example, the concentration of acid 3a present in the
blood at Tmax is 30 times higher than the parent drug for
compound 15a and 23 times higher for compound 17a.
R1
R1
a
R1
b,c
N
N
N
Br
H
N
O
2 R1 =SO2Me
2a R1 =CN
12
11
S
d
R1
R1
N
e
N
R2
N
R2
N
14-19
13
S
S
O
O
We then tried to circumvent this metabolic degradation
through the introduction of electron-withdrawing sub-
stituents onto the phenyl ring adjacent to the site of
metabolism (Table 4). The addition of a fluorine led to
Scheme 2. Reagents and conditions: (a) 3-formylbenzeneboronic acid,
Pd(PPh3)4, Na2CO3, DME, 80 ꢁC; (b) 4-methylthioaniline, EtOH,
reflux; (c) NaBH3CN, EtOH; (d) acyl chloride, DMAP, Et3N, CH2Cl2,
or isocyanate, DBU, THF, or 4-fluorobenzyl bromide, NaH, DMF; (e)
oxone, THF/MeOH/H2O.
Table 5. Biological data for derivatives 24–30
S
O
O
N
R
N
S
O
O
a
b
Compound
R
GST-PDE IVQT IC50 (nM)
HWB IC50
(lM)
A
B
C
D
O
24
25
10
4.2
41
6.7
2.0 ( 0.8)
0.8 ( 0.5)
O
1.6
0.6
0.6
17
12
1.4
1.8
O
26
2.3
0.56 ( 0.2)
F
F
(racemic)
O
27
28
15
5.8
0.5
51
7.0
0.7
1.4 ( 0.4)
(enantiomer A)
O
1.8
7.5
0.25 ( 0.07)
F
(enantiomer B)
O
29
30
1.5
2.1
0.4
0.7
5.9
0.5
1.7
0.27 ( 0.08)
0.21 ( 0.06)
HO
O
14
N
a Values are means of two experiments.
b Values are means of three experiments, standard deviation is given in parentheses.

2612
P. Lacombe et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2608–2612
the equipotent analog (22), while the introduction of the
larger chlorine substituent (21) resulted in a dramatic
loss in potency. Furthermore, these substitutions failed
to block the oxidative cleavage of the molecule. Howev-
er, the appendage of a methyl group directly onto the
benzylic position (by using MeLi in THF at À78 ꢁC in-
stead of step (c) in Scheme 2) provided us with the de-
sired metabolic stability with minimal loss in HWB
potency.
References and notes
1. (a) Yuasa, K.; Kanoh, Y.; Okumura, K.; Omori, K. Eur. J.
Biochem. 2001, 268, 168; (b) Soderling, S. H.; Beavo, J. A.
Curr. Opin. Cell Biol. 2000, 12, 174; (c) Claveau, D.; Chen,
S. L.; O’Keefe, S.; Zaller, D. M.; Styhler, A.; Liu, S.;
Huang, Z.; Nicholson, D. W.; Mancini, J. A. J. Pharmacol.
Exp. Ther. 2004, 310(2), 752.
2. (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, 28(4), 513.
Having resolved the metabolic stability issue with this
type of tether, a series of amide derivatives were pre-
pared (Table 5). As exemplified by the acetamide deriv-
ative 24, smaller groups led to less potent compounds.
By reintroducing bulkier groups, like 4-fluoro-benzoyl
(i.e., derivative 26), we were able to regain the desired
potency on the enzyme as well as in the HWB assay.
3. Burnouf, C.; Pruniaux, M.-P.; Szilagyi, C. M. Ann. Rep.
Med. Chem. 1998, 33, 91.
4. (a) Hughes, B.; Howat, D.; Lisle, H.; Holbrook, M.; James,
T.; Gozzard, N.; Blease, K.; Hughes, P.; Kingaby, R.;
Warrellow, G.; Alexander, R.; Head, J.; Boyd, E.; Eaton,
M.; Perry, M.; Wales, M.; Smith, B.; Owens, R.; Catterall,
C.; Lumb, S.; Russell, A.; Allen, R.; Merriman, M.;
Bloxham, D.; Higgs, G. Br. J. Pharmacol. 1996, 118,
1183; (b) Perry, M. J.; O’Connell, J.; Walker, C.; Crabbe,
T.; Baldock, D.; Russell, A.; Lumb, S.; Huang, Z.; Howat,
D.; Allen, R.; Merriman, M.; Walls, J.; Daniel, T.; Hughes,
B.; Laliberte, F.; Higgs, G. A.; Owens, R. J. Cell Biochem.
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Forster, C. J.; Gleason, J. G.; Bender, P. E.; Karpinski, J.
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T. Science 2000, 288, 1822.
The pharmacokinetic profile of compound 26 in rats and
in squirrel monkey was established. It showed a half-life
of 2 and 7 h, respectively, following iv administration, as
well as good oral bioavailability when dosed in 60%
PEG 200/water (67% with Cmax = 2.7 lM and 98% with
Cmax = 0.9 lM, respectively). The in vivo efficacy of 26
was then evaluated in the ovalbumin-induced broncho-
constriction assay in conscious guinea pig.8 Following
this protocol, the amide 26 showed 74% inhibition at
30 lg/kg when administered interperitoneally (ip). In
comparison, CDP-8404a,b a prototypical PDE IV inhib-
itor, which has shown efficacy in animal models as well
as in human, exhibited a 55% inhibition when dosed ip
at 1 mg/kg in this model.
´
5. Macdonald, D.; Mastracchio, A.; Perrier, H.; Dube, D.;
Gallant, M.; Lacombe, P.; Desch enes, D.; Roy, B.;
The racemic mixture 26 was resolved9 and the more po-
tent enantiomer (28) exhibited a 2-fold improvement in
intrinsic potency on PDE IV. Introduction of polar sub-
stituent (i.e., 29) or heterocycle (i.e., 30) also led to an
increase in whole blood activity.
ˆ
Scheigetz, J.; Bateman, K.; Li, C.; Trimble, L. A.; Day,
S.; Chauret, N.; Nicoll-Griffith, D. A.; Silva, J. M.; Huang,
´
Z.; Lalibert e, F.; Liu, S.; Ethier, D.; Pon, D.; Muise, E.;
Boulet, L.; Chan, C. C.; Styler, A.; Charleson, S.; Mancini,
J.; Masson, P.; Claveau, D.; Nicholson, D.; Turner, M.;
Young, R. N.; Girard, Y. Bioorg. Med. Chem. Lett. 2005,
15, 5241.
In conclusion, we have demonstrated that the intro-
duction of nitrogen containing tethers to substituted
8-arylquinolines can lead to potent inhibitors of the
PDE IV enzyme. Moreover, blocking the metabolic
degradation of those compounds by introducing a
substituent at the benzylic position gave us the desired
pharmacokinetic profile in rats and in squirrel
monkeys. Subsequently, a prototypical example of this
series, compound 26 was found to be active in an
ovalbumin-induced bronchoconstriction assay in con-
scious guinea pig and is currently been evaluated to
determine its emetic threshold.
´
6. Laliberte, F.; Han, Y.; Govindarajan, A.; Giroux, A.; Liu,
S.; Bobechko, B.; Lario, P.; Bartlett, A.; Gorseth, E.;
Gresser, M.; Huang, Z. Biochemistry 2000, 39, 6449.
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Chan, C.-C. Br. J. Pharmacol. 1999, 126, 979.
´
8. (a) Ortiz, J. L.; Valles, J. M.; Marti-Cabrera, M.; Cortijo,
J.; Morcillo, E. J. Naunyn-Schmiedeberg’s Arch. Pharmacol.
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9. Separation of the two enantiomers was performed by chiral
HPLC (Chiralpak AD 5 · 50 cm, 20 l, 60 ml/min, 40%
hexanes/60% ethanol, rt = 55 and 79 min.).