Optimization and structure-activity relationship of a series of 1-phenyl-1,8-naphthyridin-4-one-3-carboxamides: Identification of MK-0873, a potent and effective PDE4 inhibitor

Article abstract of DOI:10.1016/j.bmcl.2008.09.009

A SAR study of a series of 1-phenyl-1,8-naphthyridin-4-one-3-carboxamides is described. Optimization of the series was based on in vitro potency against PDE4, inhibition of the LPS-induced production of TNF-α in human whole blood and minimizing affinity f

Full text of DOI:10.1016/j.bmcl.2008.09.009

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5554–5558
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Optimization and structure–activity relationship of a series of
1-phenyl-1,8-naphthyridin-4-one-3-carboxamides: Identification
of MK-0873, a potent and effective PDE4 inhibitor
*
Daniel Guay , Louise Boulet, Richard W. Friesen, Mario Girard, Pierre Hamel, Zheng Huang, France Laliberté,
Sébastien Laliberté, Joseph A. Mancini, Eric Muise, Doug Pon, Angela Styhler
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:
Received 10 July 2008
Revised 1 September 2008
Accepted 3 September 2008
Available online 6 September 2008
A SAR study of a series of 1-phenyl-1,8-naphthyridin-4-one-3-carboxamides is described. Optimization of
the series was based on in vitro potency against PDE4, inhibition of the LPS-induced production of TNF-
a
in human whole blood and minimizing affinity for the hERG potassium channel. From these studies, com-
pounds 18 and 20 (MK-0873) were identified as optimized PDE4 inhibitors with good overall in vitro and
in vivo profiles and selected as development candidates.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
PDE4
Type 4 phosphodiesterase
1,8-Naphthyridin-4-one-3-carboxamides
Asthma
COPD
MK-0873
Cyclic nucleotide phosphodiesterases (PDEs) constitute a large
family of enzymes responsible for the hydrolysis and consequent
deactivation of the secondary messengers adenosine and guano-
sine 30,50-cyclic mono-phosphates (cAMP and cGMP, respectively).1
In humans, there are many different PDE isoforms classified into 11
families according to their substrate specificity, sequence similar-
ity and sensitivity to endogenous or exogenous regulators.2 En-
coded by 4 genes, the cAMP specific PDE4 isozymes (A, B, C and
D) are abundant in many inflammatory, immune and airway
smooth muscle cells.3 Inhibition of this enzyme significantly in-
creases the intracellular levels of cAMP resulting in the down-reg-
ulation of inflammatory cell activity in vitro and in vivo,2c,4 and has
been found to be anti-inflammatory and bronchodilatory in animal
models.5 The development of selective PDE4 inhibitors has re-
cently attracted much interest for the treatment of various diseases
including asthma and COPD and many compounds have been re-
ported in clinical development.6,7
(Fig. 1). More recently, we reported the discovery of a new struc-
tural class of highly potent and well tolerated PDE4 inhibitors
based on substituted 8-arylquinoline as exemplified by compound
3.9
As part of our medicinal chemistry program, one objective was
to identify yet another structural class of potent PDE4 inhibitors
with a decreased potential to induce emesis or to prolong the
QTc interval at doses well above that required for efficacy in animal
models. Having successfully modified an emetic PDE4 inhibitor
into a more elaborate 8-arylquinoline derivative 3 with a much im-
proved therapeutic index,9 we thought we could apply our findings
relative to potency and adverse effects to a different structural ser-
ies. Our search then focused on identifying a bicyclic heterocyclic
core to replace the quinoline moiety. At the time, a recent publica-
tion on 1,8-naphthyridin-4-ones derivatives as PDE4 inhibitors at-
tracted our attention.10 Examples such as the dichloropyridyl
amide 4 were reported to have good in vitro potency so we sought
to explore how our modifications that were successful in the quin-
oline series would apply to this new core template. Herein, we de-
scribe our medicinal chemistry efforts on the naphthyridinone
class of PDE4 inhibitors. The optimized compounds show efficacy
and a therapeutic window similar to that of other known inhibitors
considered to have low potential for adverse events.
In previous communications, we described how we optimized
the lead compound CDP-840 (1) with respect to PDE4 inhibitory
potency, metabolism issues and pharmacokinetic properties while
reducing the potential to induce emesis and to significantly pro-
long the QTc interval in vivo.8 This work led to the identification
of L-869,298 (2), a potent, selective and orally active PDE4 inhibitor
The general method used for the preparation of 1-aryl-1,8-
naphthyridin-4-one-3-carboxylate is illustrated in Scheme 1. Reac-
tion of 2-chloronicotinoyl chloride with the dianion of monoethyl
* Corresponding author. Tel.: +1 514 428 8652; fax: +1 514 428 4900.
E-mail address: daniel_guay@merck.com (D. Guay).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.09.009

D. Guay et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5554–5558
5555
O
N
O
R
R1
R2
R3
R1
O
N
R2
F2HCO
H
H
H
H
H
H
H
9a
O
R
N
O
H3CO
i-Pr
i-Pr
i-Pr
i-Bu
i-Pr
i-Pr
9b (Br=H)
N
H
H
H
9c
9d
9e
9f
S
Br
N
Me
H
H
N
H
R3
OH
H
F3C
H
CF3
9
H
Me
H
H
CDP840 1
L-869,298 2
H
Me
9g
Cl
Figure 2. List of 1-(3-bromo)phenyl-1,4-naphthyridin-4-one-3-carboxamides.
SO2Me
O
N
O
N
N
N
H
Cl
O
N
CONHR
O
N
CONHR
N
N
N
a
N
O
Cl
N
O
MeO2S
4
3
Br
Figure 1. Recently reported PDE4 inhibitors.
9
10a R = i-Propyl
10b R = 3,4-diCl-Pyridyl
malonate affords the b-ketoester 5,11 which is then treated with
triethyl orthoformate and acetic anhydride at reflux to give the
one-carbon homolog enol ether 6.12 Without purification, the eth-
oxy group is displaced with an aniline to give the corresponding
enamino ketoester 7. Cyclisation with sodium hydride in tetrahy-
drofuran yields the substituted ethyl 1-phenyl-1,8-naphthyridin-
4-one-3-carboxylate which is subsequently hydrolyzed to the
corresponding carboxylic acid 8. Formation of amide 9 was accom-
plished using conventional coupling chemistry, usually via a mixed
anhydride. In cases of deactivated or sterically congested amines,
successful coupling required prior deprotonation of the amine with
sodium hydride followed by reaction with the preformed acid
chloride.
Scheme 2. Synthesis of compounds 10a and 10b. Reagents and conditions: (a) 3-
(CH3CO)PhB(OH)2, 2M Na2CO3, Toluene, EtOH, (Ph3P)2PdBr2 cat, reflux.
R
O
N
O
N
H
10c
10d
3-OEt
N
4-SMe
10e
10f
4-COMe
4-SO2Me
R
Figure 3. List of isopropyl 1-biphenyl-1,8-naphthyridin-4-one-3-carboxamide
derivatives.
O
O
COCl
Cl
COOEt
COOEt
OEt
a
b
R
N
R
N
Cl
R
N
Cl
The 7-methyl derivative 9g (Fig. 2) was prepared starting with
5-methyl-2-chloronicotinoyl chloride whereas 9d was obtained
6
5
by
coupling
of
8
(R = H
and
X = 3-Br)
with
N-
isopropylmethylamine.
O
O
N
Biaryl derivatives such as 10a and 10b were prepared by cou-
pling of the 3-acetyl phenylboronic acid derivative with the corre-
sponding carboxamide of bromophenyl 9 (Scheme 2). Other
biphenyl derivatives 10c–f (Fig. 3) were prepared using similar Su-
zuki–Miyaura coupling reactions of 9.
COOEt
NH
COOH
c
d, e
R
N
Cl
R
N
X
X
For a direct comparison with quinoline derivative 3, we synthe-
sized the corresponding naphthyridinone analog 13 (Table 1). The
required aniline 12 was prepared starting from 3-nitrobenzalde-
hyde and the known oxadiazole 11 (Scheme 3).9
Replacement of the biphenyl moiety in 10 with a phenylpyri-
dine was easily accomplished by Suzuki–Miyaura coupling of
bromophenyl 9 with the appropriate pyridyl boronic acid (Scheme
4). Sonogashira coupling of 9 with various alkynes afforded the
corresponding phenyl aryl alkynes.
7
8
O
N
CONHR1
f
R
N
or g, h
X
In this letter, only the intrinsic inhibitory potency of com-
pounds on PDE4A is reported. As found for other structural series,
these derivatives are essentially non-selective with respect to the
inhibition of the PDE4 isozymes (less than a 5-fold difference in
the IC50 values for inhibition of PDE4A compared to PDE4B, PDE4C
and PDE4D; data not shown). The functional activity of these com-
9
Scheme 1. Synthesis of 1,4-naphthyridin-4-one-3-carboxamide template. Reagents
and conditions: (a) CH2(COOEt)COOH, n-BuLi, THF, ꢀ70 oC to rt then HCl/H2O; (b)
CH(OEt)3, Ac2O, 130 oC; (c) (X)-PhNH2, CH2Cl2, rt (d) NaH, THF; (e) NaOH, THF, EtOH,
H2O; (f) i-BuOCOCl, Et3N, THF, 0 oC, then RNH2, rt; (g) SOCl2, THF, reflux; (h) R1NH2,
NaH, DMF, rt for 30 min, then added to ArCOCl, rt.

5556
D. Guay et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5554–5558
Table 1
N
O
Potency in enzyme and whole blood assays and affinity for the hERG potassium
channel for compounds 3, 4, 9, 10 and 13a
N
H2N
a, b
N
Compound
GST-PDE4A248
IC50 (nM)
HWB
IC50
hERG bindingd
IC50 (lM)
b
c
(l
M)
O
MeO2S
N
MeO2S
3
4
13
9ª
9b
9c
9d
9e
9f
9g
10ª
10b
10c
10d
10e
10f
1.4 ( 0.5)
0.45 ( 0.2)
0.06 ( 0.02)
141 ( 9.5)
15.3 ( 0.6)
9.2 ( 1.1)
>1000
3.54 ( 0.1)
66.5 ( 9.1)
>1000
0.37 ( 0.1)
0.17 ( 0.1)
1.54 ( 0.1)
0.75 ( 0.3)
0.34 ( 0.1)
0.62 ( 0.2)
0.16 ( 0.02)
0.18 ( 0.07)
0.003 ( 0.001)
nd
0.70 ( 0.1)
0.70 ( 0.1)
nd
2.10 ( 0.9)
nd
nd
0.47 ( 0.08)
0.005 ( 0.001)
0.84 ( 0.2)
0.65 ( 0.1)
0.075 ( 0.1)
0.069 ( 0.01)
49.9
11
12
0.198 ( 0.002)
0.68 ( 0.08)
>94.5
71.5
31.6 ( 0.4)
nd
31.8 ( 1.7)
nd
nd
6.96 ( 0.5)
0.74 ( 0.02)
2.7
Cl
O
N
O
N
N
H
Cl
N
scheme 1
N
O
0.96
8.95 ( 0.4)
23.0 ( 1)
N
MeO2S
13
a
Values are single determinations or means of two or more experiments,
standard error (nd, not determined).
Assayed against the human PDE4A isoform using a construct representing the
Scheme 3. Synthesis of compound 10. Reagents and conditions: (a) 11, piperidine,
3-nitrobenzaldehyde; toluene, reflux; (b) SnCl2, EtOH, reflux.
b
common region of spliced variants expressed as a GST-fusion protein in Sf9 cells.15
c
Inhibition of LPS-induced TNF-a
production in human whole blood.4b
O
Displacement binding assay of
[
35S]-radiolabeled MK-499 in membranes
d
CONHR
O
N
derived from HEK293 cells stably transfected with the hERG gene and expressing
the IKr channel protein.16
CONHR
N
N
a
N
pounds is measured by their ability to inhibit the LPS-induced pro-
R
N
duction of TNF-a
in human whole blood.4b
Br
O
9
As we began this SAR investigation of 1-phenyl-1,8-naphthyri-
din-4-ones, we sought to compare this core scaffold with the
quinoline template we recently reported. As indicated in Table 1,
the prototypical 1,8-naphthyridinone compound 4 is 3-fold more
potent intrinsically than the substituted 8-arylquinoline com-
pound 3 against PDE4A whereas both inhibitors have equivalent
functional activity in human whole blood. However, compound 4
displays very high affinity for the voltage-gated potassium (K+)
channel encoded by the human ether-a-go-go related gene (hERG).
This ion channel mediates the rapidly activating component of the
delayed rectifier potassium current (IKr).13 Blockade of hERG can
lead to delayed repolarisation of the ventricle and hence an in-
crease in the electrocardiographic QT interval. Longer QT is a
known risk factor for a particular polymorphic ventricular arrhyth-
mia known as Torsade de Pointe. Recent reports show that many
drugs that exhibit prolongation of the QTc interval do so by block
of the hERG K+ channel.14 In exploring this new series, the affinity
of compounds for this channel, as measured in a radioligand dis-
placement binding assay, was taken as an indicator for their poten-
tial for causing QTc interval prolongation. Our goal was then to
identify structural modifications of 4 that maintained or improved
the inhibitory potency against PDE4 while reducing its affinity for
the hERG K+ channel.
b
CONHR
N
N
Ar
Scheme 4. Synthesis of pyridyl and acetylenic derivatives. Reagents and condi-
tions: (a) pyridylboronic acid, 2M Na2CO3, (Ph3P)2PdCl2 cat, EtOH, toluene, reflux;
(b) HCCAr, Et3N, CuI, (Ph3P)2PdCl2 cat, DMF, heat.
3-carboxamide group and its effect on the in vitro profile. Although
not a particularly potent inhibitor of PDE4, the more polar primary
amide 9a is completely devoid of affinity for the hERG K+ channel.
The preference for a secondary carboxamide is obvious when one
compares with substituted amides. The isopropyl derivative 9c
exhibits a 15-fold increase in potency against PDE4 relative to 9a
with only moderate affinity for the potassium channel. In contrast,
tertiary amide 9d is at least 100 times less potent as a PDE4 inhib-
itor and this may illustrate the requirement for the N–H bond or
may result from a steric congestion caused by the methyl group.
Addition of a methylene as in the isobutyl amide 9e results in a
compound 3 times more potent than 9c. However, this increase
in potency does not translate in terms of functional activity. In fact
the isobutyl amide 9e is actually 3 times less active than the iso-
propyl analog 9c in the human whole blood assay with an IC50 of
Hoping to find
a synergistic effect on potency without
significant affinity for the hERG K+ channel, we initially prepared
derivative 13 combining the aryl substituted vinyl moiety of 3 with
the prototypical 1,8-naphthyridinone compound 4 (Table 1). In-
deed, the intrinsic potency and the functional activity of this hy-
brid structure are significantly improved (8-fold and 60-fold,
respectively). Unfortunately, this compound still retains unaccept-
able affinity for the potassium channel and clearly, we needed to
identify structural features key to the desired activity and selectiv-
ity profile.
2.1 lM. This exemplifies the potential for protein shift associated
with cellular assays with certain compounds and when factored
in, would predict a decrease of in vivo efficacy.
We also investigated the effect of adding substituents directly
on the 1,8-naphthyridin-4-one core but quickly realized that such
modifications were not tolerated. For example, introduction of a
methyl at the 7-position as in 9g resulted in complete loss of
PDE4 activity.
The first phase of our SAR investigation involved the evaluation
of simple derivatives related to 4 in order to define the optimal
substitution pattern. We began by examining variations of the

D. Guay et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5554–5558
5557
Table 2
Analogous to other templates investigated such as the 8-aryl-
quinolines, the presence of a lipophilic group on the phenyl in
the meta-position is not only well tolerated but leads to a signifi-
cant increase in potency (vide infra). On the other hand, the addi-
tion of another group at the para-position such as a 4-methyl group
leads to 7-fold decrease of potency (9f vs 9c).
Having identified the optimal substitution pattern of the parent
bicyclic template, we decided to continue our SAR and further ex-
plore the meta-position by preparing a number of substituted
biphenyl analogs. These modifications invariably led to increased
inhibitory potency against PDE4 (10a–f). For example, the biphenyl
methyl ketone 10a is intrinsically 40 times more potent than the
simple phenyl analog 9b. However, once again this improvement
does not translate in the functional assay (HWB IC50 0.47 vs
Potency and binding affinity to the hERG potassium channel for pyridine derivatives
14–21
O
N
O
N
H
N
R
Compound
R
HWB
IC50
hERG binding
IC50 M)
(lM)
(l
14
0.67 0.16
0.16 0.06
0.14 0.04
18.6 2.1
34.0 4.0
13.6 2.1
0.7 lM) and is accompanied by an increased affinity (10-fold) for
N
the hERG K+ channel. A more dramatic effect on the PDE4 potency
and functional activity of these derivatives is observed when one
combines lipophilic substituents on the phenyl with the non-polar
carboxamide moiety found in 4. The dichloropyridyl amide 10b is
two orders of magnitude more active than the isopropyl amide 10a
in human whole blood with an IC50 of 5 nM. Unfortunately, as ob-
served with 13 (vide infra), this compound also has increased affin-
ity in the hERG binding assay. In fact, this is a general trend
observed within this series of 1,8-naphthyridin-4-one derivatives
where more lipophilic compounds tend to have an increased affin-
ity for the potassium channel (cf. 10c and 10d). Moving the acetyl
group from the 3- to the 4-position resulted in a derivative equally
potent against PDE4 but with 6-fold increased activity in human
whole blood (10a vs 10e). Changing this methyl ketone for a
methyl sulfone (10f) maintained very good functional activity
(IC50 = 69 nM) while significantly reducing the compounds’ affinity
for the hERG K+ channel.
15
16
N
N
S
O O
17
18
19
20
21
0.066 0.01
0.12 0.02
0.16 0.02
0.18 0.03
0.30 0.08
36.6 7.8
50.1 1.8
16.7 2.8
65.7 17
89.4 5.6
N
OH
N
O
OH
N
Encouraged by this result, we wished to further increase the
polarity of the biaryl moiety by introducing substituted heterocy-
cles such as pyridines. An added benefit to this modification would
be the possibility of salt formation in order to increase the solubil-
ity of the compounds. For the next phase of our SAR, we elected to
slightly modify the parent scaffold and replace the 3-isopropyl car-
boxamide with a cyclopropyl analog for increased metabolic stabil-
ity. The rationale for this change was the observation that the
O
N
isopropyl amide suffered from oxidative metabolism (a-hydroxyl-
ation) and hydrolysis to the primary amide in vitro and in vivo in
rats, resulting in poor pharmacokinetics. This metabolic pathway
was greatly reduced with the cyclopropylamide moiety and signif-
icantly improved the half-life of the compounds.
N
O
OH
Incorporation of a phenyl-pyridine motif resulted in compounds
with low affinity for the potassium channel; the 3-pyridyl isomer
15 being 4-fold more potent in the functional assay than the 4-pyr-
idyl analog 14 (Table 2). Addition of a variety of substituents such
as a methyl sulfone (16) maintained the activity and selectivity
profile. A significant improvement was noticed with the dimethyl
carbinol derivative 17 as this PDE4 inhibitor has an IC50 of 66 nM
in human whole blood and exhibits low affinity for the hERG K+
tent to the parent pyridine but exhibits less affinity for the potas-
sium channel (19 vs 20).
Based on these results and on preliminary pharmacokinetic
data, we selected pyridine N-oxides 18 and 20 for further evalua-
tion. Their comparative in vitro profiles along with that of previous
candidate 3 are listed in Table 3. All three compounds have similar
intrinsic potency against PDE4 and good functional activity in hu-
man and squirrel monkey whole blood.
While these three compounds are neither inhibitors nor induc-
ers of the ubiquitous cytochrome P450 3A4 enzyme, we found that
18 and 20 are much less potent at inhibiting the 2C9 isozymes than
3. Both derivatives 18 and 20 are very well absorbed in rats and
dogs resulting in excellent bioavailability (87–100%). Their half-
lives of 1.5–2 h are slightly shorter compared to 3. In squirrel mon-
key, the pharmacokinetic profiles are nearly identical for all three
compounds.
channel (IC50 = 37 lM). Unfortunately, this compound suffered
from a very short half-life (T1/2 < 30 min) when dosed in rats. When
we prepared its corresponding pyridine N-oxide 18, we were
pleased to find that this analog is only 2-fold less potent than the
parent pyridine. In fact, 18 is the major metabolite of 17 observed
in vivo and this pyridine N-oxide has a better pharmacokinetic pro-
file with good exposure and longer half-lives (vide infra). In addi-
tion, 18 has even less affinity for the hERG K+ channel than the
parent pyridine 17. Further expanding the scope of this SAR, we
also introduced an acetylenic spacer in the biaryl moiety to give al-
kyne pyridine derivatives (cf. 19–21). This modification main-
tained good inhibitory potency in the human whole blood assay
(cf. 15 vs 19 and 18 vs 21). Again, the pyridine N-oxide is equipo-
The emetic thresholds of these compounds were evaluated in
squirrel monkey by measuring the peak plasma concentration fol-
lowing an oral dose causing emesis. Similar to 3, we found 18 and

5558
D. Guay et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5554–5558
Table 3
References and notes
In vitro and in vivo profiles of 3, 18 and 20
1. (a) Yuasa, K.; Kanoh, Y.; Okumara, K.; Omori, K. Eur. J. Biochem. 2001, 268, 168;
3
18
20
(b) Soderling, S. H.; Beavo, J. A. Curr. Opin. Cell Biol 2000, 12, 174.
2. (a) Essayan, D. M. J. Allergy Clin. Immunol. 2001, 108, 671; (b) Omori, K.; Kotera,
J. Circ. Res. 2007, 100, 309; (c) Beavo, J. A.; Houslay, M. D.; Francis, S. H. Cyclic
Nucleotide Phosphodiesterases Health Dis. 2007, 3; (d) Beavo, J. Ann. Rev. Biochem.
2007, 76, 481.
3. (a) Houslay, M. D.; Adams, D. R. Biochem. J. 2003, 370, 1; (b) Houslay, M. D.;
Schafer, P.; Zhand, K. Y. J. Drug Discov. Today 2005, 10, 1503.
4. (a) 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, 752; (b)
Brideau, C.; Van Staden, C.; Styhler, A.; Rodger, I. W.; Chan, C. C. Br. J. Pharmacol.
1999, 126, 979.
5. (a) Essayan, D. M. Biochem. Pharmacol. 1999, 57, 965; (b) Souness, J. E.; Aldous,
D.; Sargent, C. Immunopharmacology 2000, 47, 127; (c) Jones, T. R.; McAuliffe,
M.; McFarlane, C. S.; Piechuta, H.; Macdonald, D.; Rodger, I. W. Can. J. Physiol.
Pharmacol. 1998, 76, 210; (d) Danahay, H.; Broadley, K. J. Clin. Exp. Allergy 1998,
28, 513.
6. Zhang, K. Y. J.; Ibrahim, P. N.; Gillette, S.; Bolag, G. Exp. Opin. Ther. Targets 2005,
9, 1283.
7. (a) Boswell-Smith, V.; Spina, D. Curr. Opin. Invest. Drugs 2005, 6, 1136; (b)
Odingo, J. O. Exp. Opin. Ther. Patents 2005, 15, 773.
GST-PDE4A248 (IC50, nM)
1.4
6.2
6.7
Whole blood TNF-a (IC50, nM)
Human
Squirrel monkey
161
11
50
123
7
50
59
178
23
66
hERG binding (IC50
,
lM)
CYP450 2C9 inhibition (IC50
,
lM)
61.0
41
Pharmacokineticsa—T1/2 (F)
Rat
Dog
4 h (95%)
5 h (55%)
4 h (33%)
3.0
10
270
1.5 h (87%)
2 h (100%)
4 h (33%)
3.7
2
530
69
84
2 h (98%)
2 h (100%)
5 h (38%)
5.1
2
220
65
84
Squirrel monkey
Emesisb Cmax
(lM)
Dose (mg/kg)
Ratio (Cmax/IC50
)
Guinea pigc (% inhibition)
Sheepd (%inhibition)
53
92
a
Half-life (T1/2) and bioavailability (F) determined following po and iv adminis-
tration of test compound.
b
In a dose ranging study (rising dose po), the maximal drug plasma level mea-
sured after the first episode of emesis in at least one animal (n > 2). See Ref. 17.
Mean % inhibition of the ovalbumin-induced bronchoconstriction in conscious
guinea pigs dosed 0.03 mg/kg ip 30 min prior to challenge (n > 5). See Ref. 5d.
8. Friesen, R. W.; Ducharme, Y.; Ball, R. G.; Blouin, M.; Boulet, L.; Côté, B.; Frenette,
R.; Girard, M.; Guay, D.; Huang, Z.; Jones, T. R.; Laliberté, F.; Lynch, J. J.; Mancini,
J.; Martins, E.; Masson, P.; Muise, E.; Pon, D. J.; Siegl, P. K. S.; Styhler, A.; Tsou, N.
N.; Turner, M. J.; Young, R. N.; Girard, Y. J. Med. Chem. 2003, 46, 2413. and
references cited therein.
c
d
Mean % inhibition of the late-phase Ascaris-induced bronchoconstriction in
9. Macdonald, D.; Mastracchio, A.; Perrier, H.; Dubé, D.; Gallant, M. l.; Lacombe, P.;
Deschênes, D.; Roy, B.; Scheigetz, J.; Bateman, K.; Li, C.; Trimble, L. A.; Day, S.;
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as estimated by the high ratio of the emetic threshold Cmax over the
IC50 for inhibition of TNF-a in squirrel monkey whole blood (Table
3).
Finally, we evaluated the in vivo efficacy of these 1,8-naphthy-
ridinone derivatives in two models of asthma. Intraperitoneal
administration of either 18 or 20 produced potent and dose-depen-
dent inhibition of the ovalbumin-induced bronchoconstriction in
sensitized guinea pigs. Similarly, both compounds protected
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In summary, we have identified a series of 1-phenyl-1,8-naph-
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