Design, synthesis, and biological evaluation of 8-biarylquinolines: A novel class of PDE4 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.01.004

The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC₅₀ < 10 nM) isozymes (A-D). In a human whole blood in vitro assay, they inhibit (IC₅₀ < 0.5 μM) the LPS-induced release of the cytokine TNF-α. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.

Full text of DOI:10.1016/j.bmcl.2008.01.004

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 1407–1412
Design, synthesis, and biological evaluation of 8-biarylquinolines:
A novel class of PDE4 inhibitors
Michel Gallant,* Nathalie Chauret, David Claveau, Stephen Day, Denis Descheˆnes,
´
´
´
Daniel Dube, Zheng Huang, Patrick Lacombe, France Laliberte, Jean-Franc¸ois Levesque,
Susana Liu, Dwight Macdonald, Joseph Mancini, Paul Masson, Anthony Mastracchio,
´ `
Donald Nicholson, Deborah A. Nicoll-Griffith, Helene Perrier, Myriam Salem,
Angela Styhler, Robert N. Young and Yves Girard
Merck Frosst Center for Therapeutic Research, Department of Medicinal Chemistry, PO Box 1005, Pointe Claire—Dorval,
Que., Canada H9R 4P8
Received 12 November 2007; revised 21 December 2007; accepted 2 January 2008
Available online 8 January 2008
Abstract—The structure–activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4)
inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct
PDE4 (IC50 < 10 nM) isozymes (A–D). In a human whole blood in vitro assay, they inhibit (IC50 < 0.5 lM) the LPS-induced release
of the cytokine TNF-a. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model
in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in
squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including
a good therapeutic window of efficacy over emesis.
Ó 2008 Elsevier Ltd. All rights reserved.
The phosphodiesterase (PDE) superfamily of cyclic
nucleotide (cAMP and cGMP) hydrolyzing enzymes is
composed of at least 11 members.1 These enzymes are
widely distributed in various cells, but the PDE4 sub-
types are specifically found in inflammatory cells in-
volved in the pathogenesis of diseases such as asthma,
COPD, and rheumatoid arthritis.2 Inhibition of PDE4
leads to an increase in intracellular cAMP which in turn
inhibits the release of inflammatory mediators such as
cytokines (TNF-a, IL-2, IL-12, LTB4, IFN-c) as well
as the recruitment and activation of inflammatory cells.3
This observation can be replicated in vitro by measuring
the ability of PDE4 inhibitors to block the LPS-stimu-
lated TNF-a release in human whole blood thus allow-
ing a direct measurement of their relative potency.4
Intrinsic potency of inhibitors against the four PDE4
isozymes A, B, C, and D was assessed using PDE4-
GST constructs, expressed in SF9 cells via the baculovi-
rus expression system.5
Despite the pre-clinical and clinical evidence that PDE4
inhibitors represent a valuable therapeutic approach for
the treatment of inflammatory-related respiratory dis-
eases,6 they are often associated with adverse effects such
as nausea and emesis.7 The work described in this paper
aimed at identifying potent PDE4 inhibitors with an im-
proved therapeutic index of efficacy over emesis in pre-
clinical models. The in vivo efficacy of these inhibitors
was assessed in an ovalbumin-induced bronchoconstric-
tion model in conscious guinea pig,8 while their propen-
sity to produce an emetic response was evaluated by
performing pharmacokinetic studies in squirrel
monkeys.
Strategies to identify PDE4 inhibitors with a good ther-
apeutic window of efficacy over emesis have been
numerous. For examples, efforts have been made to
identify isozyme-selective inhibitors,9 to pinpoint the
molecular target of emesis versus efficacy by using
highly emetic photoaffinity probes10 or finally to focus
on peripherally restricted inhibitors.11 Our approach
Keywords: Phosphodiesterases type 4; Inhibitors; Respiratory diseases;
Emesis.
*
Corresponding author. Tel.: +1 514 428 3054; fax: +1 514 428
4939; e-mail: michel_gallant@merck.com
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.01.004

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M. Gallant et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1407–1412
consisted in identifying a novel scaffold of PDE4 inhibi-
tors by combining known pharmacophores in the public
domain which display low incidence of emesis with highly
potent ones. This strategy ultimately leads to discovery of
L-454560 as our first development candidate.12
and D (PDE4QT). All PDE4 inhibitors described in this
paper displayed little or no isozyme specificity.
In general, mono-substituted phenyl group exhibited
similar intrinsic potency (PDE4QT) to L-454560 but
their IC50 was shifted in presence of protein as exempli-
fied by their relative whole blood activity (TNF-a).
Moreover, they had limited effect on the affinity for
CYP 2C9. The benzyl methyl sulfone 5 showed some
improvement over L-454560 on the three parameters
of interest. Introduction of heterocycles was tolerated
with minimal loss in both intrinsic and whole blood
potency as exemplified by entries 6 to 10. The pyridine
N-oxide 7 was not a competitive inhibitor of CYP 2C9
while the imidazolo-pyridine 10 was the overall best
analog. These results suggested that reduction of CYP
2C9 affinity could be achieved by introducing polarity
on the biaryl moiety and that the addition of appendage
could modulate potency. A series of substituted pyridi-
nyl N-oxides were prepared to validate this hypothesis.
Pharmacokinetic data in rats were also generated for
each analog, given that the imidazolo-pyridine 10 was
not orally bioavailable in rats and the pyridine N-oxide
7 exhibited a short half-life.
L-454560 was found to be intrinsically highly potent
(Fig. 1) with good human whole blood (HWB) activity
but more importantly displayed a low emetic index. Spe-
cifically, L-454560 triggered an emetic response in squir-
rel monkeys (SqM) at a plasma concentration of 3.8 lM
while its IC50 in SqM whole blood is 11 nM (3800/
11 = 45). Despite these data, two issues were identified
and deemed significant enough to initiate a backup ef-
fort. First, L-454560 was found to be a competitive
inhibitor of the cytochrome P450 2C9 (IC50 = 0.2 lM)13
which could potentially lead to drug–drug interaction.
Second, the olefin at the core of L-454560 was found
to isomerize in human by the addition and elimination
of glutathione. To address this problem a series of biaryl
analogs were prepared (Table 1). The dimethyl sulfone
8-phenyl quinoline core was left unchanged as it was
previously optimized for potency and metabolic stabil-
ity. Their relative intrinsic potency is expressed as an
average of the potency for all four isozymes A, B, C,
Several permutations of the relative position of the
pyridinyl N-oxide and the appendage were explored,
but the 5 and 6 substituted 3-pyridinyl N-oxide scaffolds
were optimum for potency (Table 2). Introduction of a
methyl next to the N-oxide (entry 11) led to modest gain
in whole blood potency and bioavailability in rats. How-
ever, in rhesus monkey this analog was readily metabo-
lized to the corresponding hydroxyl–methyl analog 12.
The latter was also observed in rats but to a lesser
extent. Alcohol 12 has poor orally bioavailability in rats
and the corresponding carboxylic acid 13 has low
potency. To alleviate this metabolic instability, the
tertiary alcohol 14 was prepared. This analog exhibited
a good overall in vitro profile, an acceptable oral
bioavailability across three species (rat, dog, and mon-
key) and therefore was further profiled (see Table 4)
and assessed in our efficacy model. Introducing different
functional groups such as urea, exemplified by 15, im-
proved significantly whole blood potency but was detri-
mental to oral bioavailability. The amide analog 16 was
an acceptable compromise but with modest reduction
for CYP 2C9 affinity. The reversed amide 17 suffered from
lower bioavailability. Several 5-substituted 3-pyridinyl
N-oxides were prepared but led to no improvement on
the overall profile as compared to their 6-substituted
counterparts. Surprisingly, in several cases, low oral
bioavailability was observed as exemplified by the tertiary
alcohol 16 and the amide 19.
SO2Me
PDE4QT IC50 = 3.0 nM
HWB (TNF-α) IC50 = 0.16 μM
N
Emetic Index (Cmax / IC50) = 345
N
O
N
MeO2S
L-454560 (1)
Figure 1.
Table 1. Initial SAR on biaryl quinoline PDE4 inhibitors
SO2Me
N
a
Entry
IC50 (lM)
PDE4QT
TNF-a
CYP 2C9
2
3
4
5
6
7
8
9
–Ph-2-SO2Me
–Ph-3-SO2Me
–Ph-4-SO2Me
–Ph-4-CH2SO2Me
3-Pyridinyl
0.0026
0.0010
0.0008
0.0011
0.0042
0.030
0.70
0.31
0.60
0.12
0.32
0.58
0.52
1.1
—
0.58
0.73
1.6
In the previously described series, reduction of CYP 2C9
affinity was achieved by introducing the polar pyridine
N-oxide moiety while the addition of appendage was
shown to modulate potency. A parallel strategy in which
the polar moiety was positioned on the appendage was
also explored. Consequently, a series of analogs bearing
a carboxylic acid group were prepared (Table 3). The
benzoic and phenyl acetic acid derivatives 20 and 21 dis-
played high affinity for the PDE4 enzymes both intrinsi-
0.63
36
3-Pyridinyl N-oxide
4-Pyridinyl
4-Pyridinyl N-oxide
0.0027
0.022
0.11
—
H
N
10
0.0019
0.15
2.9
N
N
a IC50 determinations are averages of at least two experiments.

M. Gallant et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1407–1412
Table 2. SAR on substituted pyridinyl N-oxide
1409
SO2Me
N
R
5
6
N
O
a
Entry
R
IC50 (lM)
Rat PK
PDE4QT
TNF-a
CYP 2C9
Fb, T1/2
c
7
11
12
13
14
15
16
17
18
19
0.030
0.58
0.48
0.56
6.3
36
26
—
—
15
1.5
4
76, 1.2
83, 1.2
10, 1.7
—
6-Me
6-CH2OH
6-COOH
0.0099
0.012
0.107
6-C(CH3)2OH
6-NHC(O)NH-iso-propyl
6-C(O)NH-Cyclopropyl
6-NHAc
0.0068
0.0015
0.0017
0.0030
0.039
0.48
0.08
0.4
100, 1.5
11, 0.7
100, 6.5
47, 0.2
0, <1
0.12
0.82
0.85
5-C(CH3)2OH
5-C(O)NH-Cyclopropyl
0.0087
0, <1
a IC50 determinations are averages of at least two experiments.
b Bioavailability (F) is expressed in percentage (%).
c Half-life (t1/2) is expressed in hours.
Table 3. SAR on carboxylic acids
SO2Me
N
COOH
a
Entry
IC50 (lM)
Rat PK
PDE4QT
TNF-a
CYP 2C9
Fb, T1/2
c
20
21
22
23
24
25
26
27
4-
4-CH2–
0.0056
0.0029
0.0073
0.0046
0.0022
0.0015
0.0019
0.0008
0.24
0.43
25
54, 2
60, 0.3
2-CH2CH2–
3-CH2CH2–
4-CH2CH2–
4-CH2C(CH3)2–
4-C(CH3)2CH2–
4-CH(CH2)CH–
Enantiomer A
4-CH(CH2)CH–
Enantiomer B
0.92
0.33
1.8
7.2
9.8
1.6
15
25, 1
0.93
1.4
100, 2
100, 2
1.7
28
0.0014
0.60
3.2
100, 2
a IC50 determinations are averages of at least two experiments.
b Bioavailability (F) is expressed in percentage (%).
c Half-life (t1/2) is expressed in hours.
cally and in whole blood along with being orally bio-
available in rats. To identify the preferred position of
the acid residue, the three possible phenyl propionic
acids were prepared. The para-substituted analog 24
clearly emerged as the most potent one but exhibited
low oral bioavailability in rats. Rat liver microsome
incubation of the latter along with careful analysis of
the rat plasma samples following oral dosing revealed
that the major metabolic degradation pathway involved
a sequence of b-oxidation, elimination, and finally ben-
zylic oxidation leading to the benzoic acid 20.14 This
metabolic instability could easily be overcome by intro-
ducing methyl substituents at the benzylic position and
therefore restoring oral bioavailability in rats. More-
over, the resulting geminal-dimethyl acid 26 showed
low affinity for the CYP 2C9 enzyme but was highly

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M. Gallant et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1407–1412
shifted in presence of protein as exemplified by the high
ratio of whole blood over enzyme potency (0.93/
0.0007 = 13,280). This shift was even more significant
in the geminal-dimethyl analog 25. An acceptable com-
promise was reached by linking the carboxylic acid moi-
ety and the phenyl group through a trans-substituted
cyclopropane ring. The resulting racemic mixture was
resolved by chiral HPLC to afford the enantiomers 27
and 28. Both were found to be orally bioavailable but
enantiomer B (28) proved to be more potent in whole
blood and moreover showed less affinity for the CYP
2C9 enzyme. Compound 28 was ultimately further pro-
filed to determine its in vivo efficacy and emetic thresh-
old (Table 4).
mo phenylboronic acid in 50% yield. The resulting 8-
(3-bromophenyl) quinoline 30 was converted to the
corresponding pinacole boronate ester 31 in 62% yield
using pinacolato diboron in a coupling reaction cata-
lyzed by PdCl2(dppf)2. In most cases, the key interme-
diate 31 was coupled in conditions previously described
with properly substituted aryl bromide (entry 2–5, 20–
28) or 3-bromopyridine N-oxide (entry 12–19). The
pyridine derivatives 6 and 8 were prepared from the
corresponding commercially available 3 or 4-pyridine
boronic acid. Oxidation using m-CPBA led to analogs
7 and 9. Analog 11 was prepared by coupling the boro-
nic acid 43 (Scheme 2) with 30 followed by oxidation.
The imidazolo-pyridine 10 was prepared by coupling
the N-SEM protected 5 bromo imidazolo pyridine with
the pinacole boronate 31. The series of compounds
bearing an acid residue was obtained by saponification
of the corresponding ester (NaOH 1 N/THF/MeOH
at 50 °C for methyl and ethyl esters and TFA for
tert-butyl esters).
The compounds described herein were easily accessible
in a four-step sequence (Scheme 1) starting from the
previously published 8-bromo-6-[1-methyl-1-(methyl-
sulfonyl)ethyl]quinoline (29).12b The latter was coupled
via Suzuki coupling with commercially available 3-bro-
Table 4. Best overall 8-biarylquinolines
SO2Me
SO2Me
N
N
Me
OH
N
OH
O
Me
O
14
28
Guinea pig % @ lg/kgc
a
b
Entry
SqM Cmax (lM) @ dose (mpk)
SqM WB IC50 (lM)
Ratio Cmax/IC50
1
14
28
3.8 @ 10
41 @ 3
65 @ 10
0.011
0.070
0.034
345
585
53 11 @ 30 (n = 4)
69 11 @ 100 (n = 4)
62 15 @ 30 (n = 8)
1911
a Squirrel monkey plasma concentration at which emesis was observed in at least two animals.
b Ratio of SqM plasma concentration at which emesis was observed over SqM whole blood IC50
c % of inhibition of ovalbumin-induced bronchoconstriction following intra-peritoneal injection.
.
B(OH)2
SO2Me
SO2Me
(HO)2B
SO2Me
a
Br
a
N
N
N
R
Br
N
29
30
Br
Br
R
R
N
N
b
a
c
SO2Me
SO2Me
Br
SO2Me
Br
a
a
N
N
N
R
R
31
N
O
O
B
R
R
O
N
O
Scheme 1. Reagents and conditions: (a) Pd(OAc)2/PPh3 (1/3), Na2CO3, n-propanol, 80 °C; (b) Pd Cl2(dppf)2, KOAc, pinacolato diboron, DMF,
70 °C; (c) m-CPBA, CH2Cl2.

M. Gallant et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1407–1412
1411
Me
Me
the desired material only lead to a mixture of mono-
and disubstituted analogs. The trans-cyclopropyl ester
47 was prepared from the analogous cinnamate 46 using
a catalytic amount of Pd(OAc)2 to activate the olefin fol-
lowed by the addition of diazomethane in excess.
OH
Me
OH
Me
Br
32
COOMe
Br
33
Br
36
Br
38
Br
40
Br
34
Br
b
b
a
N
N
N
O
c
Me
OH
Me
OH
All other building blocks were easily prepared in one
step by amide bond formation from commercially avail-
able acids. The intermediate urea leading to 16 was pre-
pared from 5-bromo 2-aminopyridine and iso-propyl
isocyanate.
N
O
N
37
Br
39
Br
41
Me
Me
Br
35
d
b
OMe
OH
OMe
N
O
N
Br
N
N
O
O
e
f, b
To establish the full potential of the optimized 8-bia-
rylquinoline as novel therapeutic agent for the treat-
ment of inflammatory-related respiratory diseases,
the pyridine N-oxide 14 and the cyclopropane carbox-
ylic acid 28 were evaluated in the conscious guinea pig
(GP) model. Their relative susceptibility to produce an
emetic response was estimated by performing pharma-
cokinetic studies in squirrel monkeys (Table 4). In
general, whole blood IC50’s in squirrel monkeys
(SqM) are significantly lower than in human whole
blood as exemplified in Table 4. Following oral dosing
of the N-oxide 14 in squirrel monkeys at 3 mpk, an
emetic response was observed shortly after dosing
(15 min) at an average plasma concentration of 41 lM
or 585-fold over its IC50 in SqM whole blood. The N-
oxide 14 was also able to reverse by 53% the ovalbumin-
induced bronchoconstriction in guinea pigs following a
100 lg/kg intra-peritoneal administration (ip). The cyclo-
propane carboxylic acid 28 proved to be a superior PDE4
inhibitor in regard to its therapeutic index. Not only did it
show a greater ratio of plasma concentration at which
emesis was observed over the whole blood IC50 in SqM.
(65/0.034 = 1911) but it was also found to be more
efficacious in our GP model resulting in 62% inhibition
of ovalbumin-induced bronchoconstriction at a dose of
30 lg/kg ip.
CHO
N
O
Br
(HO)2B
g
N
Me
42
43
N
Me
Br
Br
45
Br
47
h
i
Me Me
O
Ot-Bu
Ot-Bu
OMe
44
Br
O
O
OMe
46
O
Scheme 2. Reagents and conditions: (a) MeMgBr, Et2O, À30 °C; (b)
m-CPBA, CH2Cl2, rt; (c) i—n-BuLi, Tol, À78 °C; ii—acetone, rt; (d)
i—n-BuLi, Tol, À78 °C; ii—CO2, rt; iii—CH2N2; (e) i—n-BuLi, Tol,
À78 °C; ii—DMF, rt; (f) NaBH4, MeOH, rt; (g) i—n-BuLi, THF,
À78 °C; ii—B(O-isopropyl)3, À78 °C–rt; iii—HCl; (h) i—n-BuLi,
cyclohexyl-isopropylamine, THF, À78 °C; ii—add 44, À78 °C; iii—
MeI, À78 °C–rt. Repeat three step sequence twice; (i) Pd(OAc)2, THF,
rt then add CH2N2 portionwise until completion.
The substituted phenyl and pyridinyl building blocks
were commercially available or prepared according to
the procedures described in Scheme 2. The N-oxide 34
was prepared in two steps by first converting methyl 5-
bromonicotinate to the corresponding tertiary alcohol
33 by addition of an excess of MeMgBr followed by oxi-
dation using m-CPBA. The analogous N-oxide 37 was
prepared in two steps. Selective lithium halogen
exchange at position 2 of 2,5-dibromopyridine using
n-BuLi at À78 °C in toluene, followed by addition of
acetone, led to the tertiary alcohol 36 which was
oxidized to the corresponding N-oxide 37 as described
before. Similarly, the ester 38 and the aldehyde 40 were
prepared by quenching the 2-lithio pyridine, respec-
tively, with CO2 (followed by CH2N2) and DMF. The
latter was reduced to the hydroxyl methyl by the action
of NaBH4 in methanol, prior to the oxidation step to
afford 41. When applicable, an aryl bromide or a bro-
mopyridine was converted to the corresponding boronic
acid by treatment with n-BuLi at À78 °C followed by the
addition of tri-isopropylboronate and subsequent
hydrolysis to the boronic acid (i.e., 43) using HCl 1 N.
The geminal-dimethyl tert-butylester 45 was synthesized
by deprotonation using the sterically hindered base
cyclohexyl isopropylamine/n-BuLi followed by addition
of iodomethane. The reaction had to be run twice to give
the desired dimethylated analog 46. Attempts to use a
large excess of base and MeI to generate in one step
In conclusion, we were able to identify two compounds
in distinct series that addressed the liabilities associated
with L-454560 (1). Both 14 and 28 were found to be less
emetic in squirrel monkeys than 1 and the acid 28 exhib-
ited superior efficacy in the guinea pig model of
bronchoconstriction.
Acknowledgments
The authors thank Dr. Dwight Macdonald and Dr.
´
Daniel Dube for proofreading this manuscript.
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´
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