Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: Structure-activity relationship, optimization, and identification of a highly potent, well tolerated, PDE4 inhibitor

Article abstract of DOI:10.1016/j.bmcl.2005.08.036

The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of em

Full text of DOI:10.1016/j.bmcl.2005.08.036

Bioorganic & Medicinal Chemistry Letters 15 (2005) 5241–5246
Discovery of a substituted 8-arylquinoline series of PDE4
inhibitors: Structure–activity relationship, optimization,
and identification of a highly potent, well tolerated, PDE4 inhibitor
*
Dwight Macdonald, Anthony Mastracchio, Helene Perrier, Daniel Dube,
´ `
Michel Gallant, Patrick Lacombe, Denis Deschenes, Bruno Roy, John Scheigetz,
´
ˆ
Kevin Bateman, Chun Li, Laird A. Trimble, Stephen Day, Nathalie Chauret,
´
Deborah A. Nicoll-Griffith, Jose M. Silva, Zheng Huang, France Laliberte,
Susana Liu, Diane Ethier, Doug Pon, Eric Muise, Louise Boulet, Chi Chung Chan,
Angela Styhler, Stella Charleson, Joseph Mancini, Paul Masson, David Claveau,
Donald Nicholson, Mervyn Turner, Robert N. Young and Yves Girard
´
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Quebec, Canada H9R 4P8
Received 15 June 2005; revised 16 August 2005; accepted 17 August 2005
Available online 15 September 2005
Abstract—The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work
has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of
emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4
(IC50 < 1 nM) and also of LPS-induced TNF-a release in human whole blood (IC50 < 0.5 lM). The same compounds are potent
inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC50 < 0.1 mg/kg ip) but require a dose of about
10 mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified
as an optimized compound.
Ó 2005 Elsevier Ltd. All rights reserved.
Type 4 phosphodiesterases, encoded by 4 genes (A to
D), are a family of cAMP-specific hydrolases responsi-
ble for the degradation of cAMP in many cell types.1
Inhibition of this enzyme can significantly increase the
intracellular c-AMP concentration, leading to various
signaling events including the inhibition of various cyto-
kines.1c For example, LPS-stimulated TNF-a release in
human blood mononuclear cells can be blocked with
PDE4 inhibitors.2 Antigen-induced bronchospasm is
another pharmacological event that can be attenuated
using PDE4 inhibitors.3 Because airway inflammation
and bronchoconstriction are major hallmarks of asthma
and COPD, PDE4 is a promising therapeutic target for
these common and serious diseases. One of the major is-
sues with the development of PDE4 inhibitors has been
the side effect of emesis observed for several prototypical
compounds.4 However, it has become clear that some
PDE4 inhibitors are less emetic than others, while pos-
sessing the same potency.4,5 That is, some PDE4 inhib-
itors have a larger therapeutic window than others.
For several years, efforts to improve the therapeutic win-
dow of PDE4 inhibitors have involved the identification
of compounds that appeared to be more potent for
inhibiting the enzyme activity and less potent on the
high affinity rolipram-binding site of the enzyme.1 More
recently, however, it has been shown that the high affin-
ity rolipram-binding site of the enzyme is simply the
cofactor (e.g., Mg2+) bound active site on the holoen-
zyme (active form of the enzyme). The conformational
difference between the PDE4 apoenzyme and the holo-
enzyme is responsible for the differential binding of
inhibitors.5d,e Other efforts have been directed toward
the identification of isozyme-selective compounds.1a
Finally, another approach which we have used was to
identify a highly emetic and efficacious photoaffinity
Keywords: PDE4; TNF-a; c-AMP; Asthma; COPD.
*
Corresponding author. Tel.: +1 514 428 3089; fax: +1 514 428
4900; e-mail: dwight_macdonald@merck.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.08.036

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D. Macdonald et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5241–5246
which are different from those of rolipram, into the 30-
position of the 8-arylquinoline (dashed boxes in
Fig. 1). The resulting hybrid compounds 5 and 6
(Fig. 2) were found to be potent PDE4 inhibitors (Table
1). Herein, we describe our medicinal chemistry efforts
on the new structural class which led to compounds with
higher potency and improved pharmacokinetics. The
optimized compounds allowed us to show that the new
structural class has a therapeutic window similar to that
of other PDE4 inhibitors that are considered to have a
low emetic potential.
O
O
O
N
N
O
8
3'
N
NH
R
O
3
4
R = OMe
R = NHSO2Ph
rolipram 2
CDP840 1
Figure 1.
The 8-bromoquinoline core 7 was prepared by condensing
either a 4-isopropyl or a methyl-substituted-2-bromoan-
iline with glycerol (Scheme 1).6 The 6-methyl-8-bromo-
quinoline 7a was further functionalized on the methyl
group by radical bromination followed by displacement
with either cyanide or methanesulfinate to give 8a and b.
Methyl groups were then introduced by activation of the
probe aimed at identifying the molecular targets of eme-
sis and efficacy for PDE4 inhibitors.8
Our medicinal chemistry objective was to identify a new
structural class of PDE4 inhibitors with a lower poten-
tial to induce emesis at a dose well above that required
for efficacy in animal models. Examples of compounds
that meet these criteria are the clinical candidates ari-
flo,5c CDP-840 1,5a,b and roflumilast.5g These com-
pounds are structural analogs of the prototypical
compound rolipram 2, which induces emesis at roughly
the same dose that is required for efficacy.4 In the pro-
cess of our work toward identifying an emetic probe,8
we discovered that introduction of a large substituent
at the 30-position of an 8-arylquinoline derivative led
to compounds with an improved emetic threshold
in the ferret, while maintaining similar potency. For
example, 36 and 48,9 (Fig. 1 and Tables 1 and 3) have
similar HWBA IC50s (8.3 and 7.8 lM, respectively).
The emetic threshold for 3 in the ferret is 1.0 mpk po
(Cmax = 0.2 lM), while 4 is non-emetic up to 10 mpk
po (Cmax = 2.0 lM).
N
N
(O)n
Cl
5 n = 0
6 n = 1
Figure 2. Hybrid molecule created by substitution of the arylquinoline
with the substituent from the catechol that leads to a non-emetic
catechol.
These observations led us to create a new structural class
by incorporating the structural features from CDP-840,
Table 1. Enzyme and human whole blood assay potency
Compound
IC50 (nM)a
PDE4A
PDE4B
PDE4C
PDE4D
HWBA
CDP 840 1
L-869,298
2.1 0.8
0.4 0.2
1.5 0.4
5.6 3.2
11.8 6.9
52 45
1.4 0.8
0.4 0.2
2.3 0.2
3.0 1.0
6.4 3.0
19 17
4.5 3.3
1.0 3.3
3.3 3.0
11.9 5.8
22 23
2.1 0.9
0.4 0.1
2.5 4.0
2.0 1.0
38 35
14
8
0.09 0.02
8.3 1.0
7.8 3.0
31 25
3
4
5
6
68 68
45 32
11
12
3
6
12
15
16
17
18
19
20
21
22a
22b
23a
23b
24
25
3.4 1.5
0.5 0.1
0.47 0.01
0.2 0.1
0.4 0.1
0.16 0.04
0.3 0.1
0.3 0.3
0.8 0.4
1.0 0.5
1.4 1.2
4.8 7.8
0.9 0.3
1.7 1.8
1.8 0.9
0.3 0.1
0.3 0.2
0.2 0.1
0.3 0.2
0.07 0.01
0.3 0.1
0.3 0.4
0.3 0.1
0.4 0.1
0.5 0.3
1.1 1.4
0.5 0.1
1.1 1.1
106 153
5.7 0.3
0.7 0.1
0.4 0.1
0.5 0.2
1.2 0.2
3.8 0.7
2.9 3.5
6.8 4.6
11.4 1.4
9.1 2.2
14 17
4.4 4.2
0.6 0.1
0.19 0.02
0.2 0.1
0.5 0.1
0.2 0.1
0.5 0.1
0.6 0.9
0.7 0.3
0.5 0.1
1.2 0.6
1.9 1.7
2.3 1.7
2.0 1.0
1.2 0.3
0.12 0.06
0.12 0.05
0.61 0.27
0.26 0.07
1.6 0.7
0.14 0.06
0.07 0.07
0.21 0.12
0.16 0.14
0.20 0.14
0.93 0.42
0.21 0.08
14
11
7
7
a Values are means of at least two experiments, standard error.

D. Macdonald et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5241–5246
5243
R
R
a
7a R = Me
7b R = i-Pr
N
H2N
N
Br
Br
e
c,d
a,b
6
5
10a
Scheme 1. Quinoline synthesis. Reagents and conditions: (a) glycerol,
sodium 3-nitrobenzenesulfonate, iron(II) sulfate heptahydrate,
methanesulfonic acid, 130 °C.
Cl
11
methylene with potassium t-butoxide followed by alkyl-
ation with iodomethane to give 9a–c (Scheme 2). The 8-
aryl substituent was introduced by the Pd-catalyzed
cross-coupling of either a commercially available aryl
boronic acid (Scheme 3), followed by further functional-
ization, or a boronate pinacol ester of a functionalized
aryl (Scheme 10).
Cl
Scheme 4. Synthesis of hybrid compounds 5–6. Reagents and condit-
tions: (a) 4-chlorophenyl magnesium bromide, THF/DCM, 0 °C; (b)
SOCl2, DIEA, benzene; (c) ethyl pyridin-4-yl-acetate, HMPA, THF,
NaHMDS; (d) NaOH; (e) mCPBA, DCM.
The saturated compounds 5 and 6 were prepared from
aldehyde10a (Scheme 4). Addition of 4-chlorophenyl
magnesium bromide was followed by conversion of the
resulting alcohol to the corresponding benzyl chloride
11 using thionyl chloride. Coupling with ethyl pyridin-
4-yl-acetate anion was followed by hydrolysis and decar-
boxylation to give the pyridine 5. Oxidation of the pyr-
idine with mCPBA afforded the pyridine-N-oxide 6.
O
O
N
B
OH
CO2Et
d,e
a-c
CO2Et
N
N
N
12
13
14
Scheme 5. Synthesis of compound 12. Reagents and conditions: (a)
HMPA, THF, NaHMDS; (b) 3-bromobenzyl bromide; (c) pinacol
diborane, Pd(dppf)Cl2, KOAc, DMF, 80 °C; (d) 7b, Na2CO3 (aq, 2N),
Pd(dppf)Cl2, DMF, 80 °C; (e) MeMgBr, THF.
Compound 12 was prepared as in Scheme 5. Coupling of
3-bromobenzyl bromide with ethyl pyridin-4-yl acetate
13 anion was followed by conversion to the boronate
pinacol ester 14. Pd-catalyzed coupling of 14 with the
8-bromoquinoline 7b followed by conversion of the ester
to the tertiary alcohol with methylmagnesium bromide
afforded compound 12.
The unsaturated compounds (15–25) were prepared as
described in Schemes 6, 8, and 10.
Compound 15 was prepared by converting pyridin-2-yl
acetic acid 26 to the methyl oxadiazole 27 followed by
a Knoevenagal condensation with the aldehyde 10a
(Scheme 6). Compounds 16–18 were prepared by elabo-
ration of the required bis-aryl ketones 29 from 28
(Scheme 7), which were then condensed with the appro-
priate benzyl phosphorous reagent (Scheme 8). In the
case of compound 18, the tertiary alcohol was intro-
duced by adding methylmagnesium bromide to the ester
in the last step. Compounds 19–25 were prepared by
elaboration of the functionalized boronate esters 30
(Scheme 9) followed by Pd-catalyzed coupling with the
respective 8-bromoquinoline 7b or 9 (Scheme 10).
a
R
d
Y
7a
b or c
N
N
Br
Br
8a Y = CN
8b Y = SO2Me
9a R = CMe2CN
9b R = CHMeSO2Me
9c R = CMe2SO2Me
Scheme 2. Functionalization at the 6-position. Reagents and condi-
tions: (a) NBS, AIBN, chlorobenzene, 70 °C; (b) KCN, DMF/water
(2:1), 100 °C; (c) sodium methanesulfinate, DMF, 25 °C; (d) potassium
t-butoxide, MeI, ꢀ78 to 25 °C.
N
N
CO2H
N
N
O
a
b
a or b
N
N
10a R = CHO
10b R = CH2OH
7b
N
26
27
N
O
N
R
15
Scheme 3. 8-Aryl coupling. Reagents and conditions: (a) (3-formyl-
phenyl)boronic acid, Pd(Ph3P)4, Na2CO3 (aq, 2 N), DMF, 80 °C; (b) 3-
(hydroxymethyl)phenylboronic acid, Pd(Ph3P)4, NaHCO3 (aq, 2 N),
DME, 80 °C.
Scheme 6. Synthesis of compound 15. Reagents and conditions: (a)
EDCI, acetamide oxime, DME, 50 °C; (b) 10a, piperidine, toluene,
reflux.

5244
D. Macdonald et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5241–5246
N
Z
Compound Reagents
29a X=CHO, a-c
X
CO2H
e,f
O
N
N
MeO2S
MeO2S
MeS
S
28
a
a
N
29b X=CHO, a,d,b,c
29c X=CHO, e,b,c
S
or a,c,d
OH
Br
O
O
N
g
N
Z
S
MeSO2
MeO2S
Z
29d
X=Br, f,b,g
29
29b
OH
CO2Me
MeO2S
Scheme 7. Synthesis of ketones 29. Reagents and conditions: (a) n-
BuLi, thiazole, THF, ꢀ78 °C; (b) MnO2, ethyl acetate, 25 °C-reflux; (c)
Oxone, THF/MeOH/H2O 2:1:1, 25 °C; (d) n-BuLi, acetone, THF,
25 °C; (e) n-BuLi, 2-bromo-5-methylpyridine, THF, ꢀ78 to 25 °C; (f)
n-BuLi, 4-carboxymethylbenzaldehyde, THF, ꢀ78 to 25 °C; (g)
mCPBA, CHCl3, 25 °C.
b
Z
Compound
30a
CO2H
O
O
B
CONH(i-Pr)
30b
30c
N
O
N
reagents
N
S
Z
30d
N
via
or
PPh3
OH
MeSO2
PO(OEt)2
Scheme 9. Synthesis of boronate esters 30. Reagents and conditions:
(a) 3-bromobenzaldehyde, piperidine, toluene, reflux; (b) diboron
pinacol ester, Pd(dppf)Cl2, KOAc, DMF, 80 °C; (c) SOCl2, TEA,
toluene, 25 °C; (d) i-PrNH2, 0 °C; (e) CDI, 25 °C; (f) acetamide oxime,
25–120 °C; (g) 3-bromobenzyltriphenyl-phosphonium bromide, THF/
DMF(2:1), LiHMDS, 0 °C.
OH
10b
Compound Reagents
Z
16a
a-c
N
S
N
N
17
d,e,c
d,e,c,f
O
O
R
B
+
Z
N
18
OH
Br
Compound
19
R
Z
MeO2S
aMixture of geometric isomers.
N
i-Pr
7b or 9
30
O
N
Scheme 8. Synthesis of compounds 16–18. Reagents and conditions:
(a) AcOH, 48% HBr, 100 °C; (b) Ph3P, MeCN, 60 °C; (c)29, t-BuOK,
THF, ꢀ78 to 25 °C; (d) MsCl, TEA, DCM, ꢀ78 °C; (e) diethylphosph-
ite, potassium t-butoxide, THF, ꢀ78 to 25 °C; (f) MeMgCl, THF,
25 °C.
20
21
i-Pr
i-Pr
CO2H
CONH(i-Pr)
a or
b (for 25)
22a/b*
23a/b*
24
CMe2CN
CONH(i-Pr)
N
R
CMe2SO2Me
CMe2SO2Me
CMeHSO2Me
O
N
N
CONH(i-Pr)
The compounds were evaluated for their inhibitory
potency on the PDE4A, B, C, and D enzymes,1c,5d and
also on LPS-induced TNF-a formation in human whole
blood (Table 1).2 For comparison, the data for CDP-840
and L-869,2985j are included.
N
S
25**
OH
*Compound a is as drawn and compound
b is the geometric isomer.
Z
MeSO2
**Mixture of geometric isomers.
Structure–activity relationship (SAR) studies on the
hybrid compounds led to the conclusion that the 4-
chlorophenyl moiety of 5 or 6 was not necessary for
activity and small polar groups, such as a hydrox-
yalkyl, a to the pyridine, lead to improved potency
(Fig. 3). This is illustrated by comparing compounds
12 and 5 in Table 1 (3.4 and 11.8 nM, respectively,
on PDE4A).
Scheme 10. Synthesis of compounds 19–25. Reagents and conditions:
(a) Pd(dppf)Cl2, Na2CO3 (2 M, aq), DMF 80 °C; (b) Pd(OAc)2, Ph3P,
Na2CO3 (2 M, aq), n-propanol, 80 °C.
The first prototypical representative in this new class,
compound 12 (Table 1), has a similar PDE4 inhibitory
potency, both on the purified enzyme and in the

D. Macdonald et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5241–5246
5245
polar substituent improves potency
(hydroxyalkyl, acyl, aryl, heteroaryl)
N
R
double bond
improves potency
aryl, heteroaryl
N
aryl not necessary
for activity
Cl
Figure 3. Structure–activity relationship of the new hybrid series.
Table 2. Pharmacokinetics of compounds in rats at 20 mg/kg po
However, these first compounds, which were optimized
for in vitro potency, were found to be metabolically
unstable in vivo leading to modest oral bioavailabity.
For example, compound 19 (Table 2) is extensively
metabolized to give two major metabolites, which have
plasma concentrations 15- to 30-fold greater than the
parent compound. LCMS analysis indicated that the
metabolites contain 1 and 2 hydroxyl groups on the iso-
propyl group. In order to prevent or reduce the metab-
olism, we prepared several isopropyl analogs. The best
modifications were those with a nitrile or a methyl sul-
fone (compounds 22–25). These have a similar potency
to the corresponding isopropyl compounds (Table 1)
but have superior pharmacokinetics in the rat with very
low levels of circulating metabolites. Examples are com-
pounds 22a and 23a in Table 2.
Compound
Cmax (lM)
Tmax (h)
F (%)
19
0.5
4.1
5.1
0.5
6
11
80
22a
23a
6
100
Dosed po in 60% PEG/water using a dose volume of 10 mL/kg.
human whole blood assay, to that of CDP-840. The
emetic threshold of 12 in the ferret is similar to that
of CDP-840 (Table 3). This compound also possesses
good bioavailability in the ferret (Cmax = 2.9 lM at
10 mpk po).
Further SAR studies in the series led to the discovery of
several modifications that either improve or maintain
the potency. These include introduction of an unsaturat-
ed link, replacement of the pyridine with a substituted
aryl or another heterocycle, and replacement of the link
substituent with an acyl, aryl, or heteroaryl (Fig. 3).
With the combination of all the best substituents, the
potency was improved by 20- to 100-fold from the lead
compounds 5 and 6 on both the purified enzyme and in
the human whole blood assay (see compounds 15–21 in
Table 1).
The emetic threshold of several of these compounds was
evaluated in the squirrel monkey and found to be similar
to that of CDP-840 1, even though the in vitro potency
(human and squirrel monkey whole blood assays) is 20-
to 200-fold greater (Tables 1 and 3). This improvement
in tolerability is illustrated by the ratio of emesis thresh-
old plasma concentration/squirrel monkey whole blood
IC50. The ratio is 9 for CDP-840 1 while the hybrid
Table 3. In vivo comparative profiles of selected compounds with CDP-840 and L-869,298
Compound Guinea piga (%) (mg/kg) Sheep early(%)/late(%)b Emesis Cmax (lM)
Squirrel monkey
whole blood IC50(lM)d Cmax/IC50
Ratioe Emesis
c
(dose mg/kg, responders)
CDP-840 1 54 (1)
L-869,298
39/88
68/92
ND
2.5 (30, 2/6)f, 4 (10, 1/4)g
1.6 (0.5, 2/4)g
0.60
0.005
ND
9
62 (0.01)
320
ND
ND
26
3
70 (0.3)
46 (1)
47 (1)
0.2 (1.0, 2/2)f
4
ND
ND
>2.0 (10, 0/2)f
2.9 (10, 1/2)f, 11.9 (10, 1/2)g 0.45
1.9 (10, 2/4)g
3.8 (10, 3/6)g
>2.5 (3, 1/2)g
ND
12
22a
23a
24
75 (0.03)
53 (0.03)
59 (0.1)
ND
73/95
ND
0.015
0.011
ND
127
345
ND
a Mean percent inhibition of ovalbumin-induced bronchoconstriction in conscious guinea pigs dosed ip 30 min prior to challenge (n = 4–8). See Ref.
3b. Dose (mg/kg) shown in brackets.
b Mean percent inhibition of early/late-phase antigen induced bronchoconstriction in Ascaris sensitive sheep (n = 2–4) dosed iv with 0.5 mg/(kg day)
of test compound for 4 days and challenged 2 h post dose on day 4. See Ref. 3c. ND = not determined.
c See Ref. 7. In a rising dose (dose ranging study), the average maximal plasma concentration (Cmax) is achieved after the first po dose in which emesis
is observed in at least one animal in the dosing group (n P 2). Dose (mg/kg) and number of responders exhibiting emesis are shown in parentheses.
d Inhibition of LPS-induced TNFa production in squirrel monkey whole blood. This assay was performed according to Ref. 2 using squirrel monkey
whole blood and employing a 4 h incubation after LPS stimulation rather than 24 h. IC50 represents the mean EM (n P 3).
e Ratio of the Cmax plasma concentration to the IC50 for inhibition of LPS-induced TNFa production in squirrel monkey whole blood.
f Ferret.
g Squirrel monkey.

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D. Macdonald et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5241–5246
1183; (b) Perry, M. J.; OÕConnell, J.; Walker, C.; Crabbe,
T.; Baldock, D.; Russell, A.; Lumb, S.; Huang, Z.; Howat,
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Underwood, D. C.; Griswold, D. E.; Cieslinski, L. B.;
Burman, M.; Bochnowicz, S.; Osborn, R. R.; Manning, C.
D.; Grous, M.; Hillegas, L. M.; Bartus, J. O.; Ryan, M.
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compounds have ratios of 26–345 (Table 3). The com-
pounds are also well absorbed with good pharmacoki-
netics in the squirrel monkey. In a guinea pig
functional model (ovalbumin induced bronchoconstric-
tion), these compounds are also 10- to 100-fold more
potent than CDP-840 1 (Table 3).
In summary, a new structural class of highly potent
PDE4 inhibitors has been discovered with a therapeutic
window between emesis and efficacy larger than that of
CDP-840 1. All of these compounds are non-selective
for the PDE4A, B, C, and D subtypes. The compound
23a (L-454,560:10 PDE4A IC50 = 1.4 nM, human whole
blood IC50 = 0.16 lM) was selected as a candidate for
further development. Compound 23a was well tolerated
in the squirrel monkey with an emesis window of 345-
fold. It was also effective in the guinea pig ovalbumin-in-
duced bronchoconstriction model (53% at 0.03 mg/kg
ip) and in the sheep ascaris-induced bronchoconstriction
model (73%/95%, early/late, 0.5 mg/kg, iv). L-869,298,5j
the most optimized analog of CDP-840, also has a bio-
logical profile similar to that of 23a.
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