Substituted 4-(2,2-Diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters

Article abstract of DOI:10.1016/S0960-894X(02)00615-7

A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phosphodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models.

Full text of DOI:10.1016/S0960-894X(02)00615-7

Bioorganic & Medicinal Chemistry Letters 12 (2002) 3009–3013
Substituted 4-(2,2-Diphenylethyl)pyridine-N-oxides as
Phosphodiesterase-4 Inhibitors: SAR Study Directed Toward
the Improvement of Pharmacokinetic Parameters
Richard Frenette,* Marc Blouin, Christine Brideau, Nathalie Chauret, Yves Ducharme,
Richard W. Friesen, Pierre Hamel, Tom R. Jones, France Laliberte, Chun Li,
Paul Masson, Malia McAuliffe and Yves Girard
´
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Quebec, Canada H9R 4P8
Received 13 March 2002; accepted 19 June 2002
Abstract—A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is
reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phos-
phodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of
animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models.
# 2002 Elsevier Science Ltd. All rights reserved.
Cyclic nucleotide phosphodiesterases (PDEs) constitute
a broad family of enzymes responsible for the hydrolysis
and consequent deactivation of the second messengers
cAMP and cGMP.1 Among this superfamily of 11 PDE
isoenzymes, the PDE type 4 (PDE4) enzymes, encoded
by four genes (A–D),2 have received particular attention
due to the fact that they are particularly abundant in
inflammatory, immune, and airway smooth muscle
cells.3,4 Since elevation of cAMP levels is known to
inhibit the activation of these cells, PDE4 inhibitors
may have potential as anti-inflammatory drugs.3c Selec-
tive PDE4 inhibitors could become promising ther-
apeutic agents for the treatment of asthma and a wide
range of other inflammatory diseases, by virtue of their
ability to block both inflammation and bronchocon-
striction.3b In fact, a number of PDE4 inhibitors are
being evaluated in the clinic and they have shown pro-
mising clinical efficacy for asthma,5 chronic obstructive
pulmonary disease (COPD)6 and atopic dermatitis.7
metabolized in vitro with a concomitant short half-life
in vivo.10 In a previous publication, we reported how
the replacement of the alkoxy substituents of the cate-
chol by the difluoromethoxy group and the substitution
of the pendant phenyl ring by the bis(trifluoromethyl)
carbinol group, transformed CDP-840 into L-791,943, a
highly potent and metabolically more stable inhibitor.11
Unfortunately, despite a good biological profile, L-
791,943 shows an excessively long half-life (>48 h) in a
variety of animal species.
We report here the results of a SAR study directed
toward the optimization of pharmacokinetic parameters
for analogues of L-791,943. Our strategy to reduce the
half-life in this series consisted in introducing soft
metabolic sites to the structure of L-791,943 as shown in
Figure 1.
In Vitro Studies
We already reported that the potent PDE4 inhibitor
CDP-840, known to significantly reduce the broncho-
constriction induced by antigen in animal models8 and
in asthmatic patients,9 was found to be extensively
Intrinsic potency of compounds were assayed against
human PDE4A248 isoform using construct representing
the common region of spliced variants expressed as GST-
fusion proteins in Sf9 cells.12 IC50 values represent a mean
of n=3 or more. The cellular potency of the compounds
was evaluated by the inhibition of the LPS-induced
TNF-a formation in human whole blood (HWB).13
*Corresponding author. Tel.:+1-514-428-8620; fax:+1-514-428-4900;
e-mail: richard_frenette@merck.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00615-7

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R. Frenette et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3009–3013
introduced and protected as its SEM ether (2a–c). When
2,5-dibromotoluene was used (1, R1=CH3), both
regioisomers 2b and 2c were available from the separa-
tion, by chromatography in pure hexane, of the mixture
of alcohols produced. The corresponding aryl Grignard
reagents of 2a–c were reacted with 3,4-(difluoro-
methoxy)benzaldehyde11 to produce the diaryl alcohols
3a–c. Treatment of the alcohols with thionyl chloride
permitted the efficient isolation, after quick chromato-
graphy in toluene, of the diaryl chlorides 4a–c.
Figure 1.
Sites of Substitution
The pyridine moiety was introduced when a chloride
solution (4a–c) in THF was treated with a solution of
the anion of ethyl 4-pyridylacetate, prepared previously
from treatment with KHMDS in the presence of
HMPA in THF. The adduct 5 was obtained as a mix-
ture of diastereomers. This mixture was usually hydro-
lyzed and acidified without separation of the
diastereomers. The decarboxylation occured during the
work-up. The pyridine derivatives 6b,c obtained were
subjected to cleavage of the SEM group with TBAF and
oxidized with MMPP to the corresponding pyridine-N-
oxides 7 and 8, existing as mixtures of enantiomers.
We evaluated the potential sites of attachment of the
soft metabolic moieties by adding first a methyl group
at various positions of L-791,943. As outlined in
Scheme 1, the first sites of attachment studied were on
the bis(trifluoromethyl)carbinol phenyl ring and on the
carbon adjacent to the pyridine ring.
Starting from the appropriate dibromobenzene deriva-
tive (1), the bis(trifluoromethyl)carbinol group was
The introduction of a methyl group on the carbon
adjacent to the pyridine ring was accomplished by
transforming the diastereomeric mixture of acetates 5a
to the corresponding tosylates. At this point, the two
diastereomers were separated by chromatography to
give 9 (diastereomer 1, fast eluting compound) and 10
(diastereomer 2, slow eluting compound). Both tosylates
were reduced to the methyl derivatives and transformed
as described above to give 11 and 12.
The compounds prepared to study the effect of the sub-
stitution of the pyridine ring were accessible by using
the appropriately substituted 4-methylpyridine analogues
(Scheme 2). Alkylation of 3,4-dimethylpyridine and
3-ethyl-4-methylpyridine with dimethyl carbonate
Scheme 1. Reagents and conditions: (a) BuLi, Et2O, À78 ꢀC, 30 min;
then (CF3)2CO, À50 ꢀC, 2 h, 70–75%; (b) SEMCl, i-Pr2NEt, CH2Cl2,
rt, 18 h, 95%; (c) Mg, THF, reflux, 1.5 h; then 3,4-(difluoromethoxy)
benzaldehyde,11 THF, À78 ꢀC, 1.5 h, 80–85%; (d) SOCl2, pyridine,
toluene, rt, 30 min, 75–85%; (e) ethyl 4-pyridylacetate, KHMDS,
HMPA, THF, rt, 3 h; then 4a–c in THF, added to previous mixture,
rt, 3 h; (f) 2 N LiOH, THF:MeOH (3:1), 65 ꢀC, 1 h; then 4 N HCl fol-
lowed by evaporation of volatiles, 50–75% (2 steps); (g) TBAF, THF,
65 ꢀC, 6 h; (h) MMPP, CH2Cl2: MeOH (10:1), rt, 3 h, 85% (2 steps).
(i) LiAlH4, THF, rt, 1 h, 90%; (j) TsCl, pyridine, rt, 7 h, 70%; fol-
lowed by flash chromatography in ethyl acetate: hexane (1:1); (k)
LiAlH4, THF, rt, 1 h, 50%.
Scheme 2. Reagents and conditions: (a) LDA, THF, À78 ꢀC, 30 min;
then dimethyl carbonate, THF, À78 to 0 ꢀC, over 1 h, 75%; (b)
KHMDS, HMPA, THF, rt, 30 min; then 4a in THF, added to pre-
vious mixture, 55 ꢀC, 18 h; (c) 2 N LiOH, THF:MeOH (3:1), 65 ꢀC, 1
h; then 4 N HCl followed by evaporation of volatiles, 60–75% (2
steps); (d) TBAF, THF, 65 ꢀC, 6 h; (e) MMPP, CH2Cl2: MeOH (10:1),
rt, 3 h, 80–90% (2 steps).

R. Frenette et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3009–3013
3011
produced, respectively, the 4-pyridylacetates 13a and
13b. Methyl 2-methyl-4-pyridylacetate (13c) was pre-
pared as reported in the literature.14 Using the same
methodology as described above, the substituted pyr-
idines 14a–c were obtained from 4a and functionalized
to give the substituted pyridine-N-oxides 15, 16, and 17.
Because of the steric factors associated with the 3,5-
dimethylpyridine moiety, the preparation of this analogue
was not accessible by the above methodology. The
preparation of the more reactive diarylbromide 18, pre-
pared from the alcohol 3a with thionyl bromide, was
necessary in combination with a more reactive nucleo-
phile, the lithium anion of 3,4,5-trimethylpyridine 19
(Scheme 3). The latter compound was prepared from
3,5-dibromopyridine, which is methylated successively
with methyl iodide, followed by a double Stille-coupling
with tetramethyltin. Coupling of the lithium anion of 19
with the diarylbromide 18 provided the dimethylpyr-
idine adduct 20 that was transformed to its pyridine-N-
oxide analogue 21 as previously described.
Scheme 4. Reagents and conditions: (a) BuLi, THF, À100 ꢀC, 10 min;
then methyl formate, À96 ꢀC to À78 ꢀC, 1 h, 95%; (b) NaBH4,
THF:MeOH (2:1), 0 ꢀC to rt, 1 h, 47%; (c) TIPSOTf, 2,6-lutidine,
CH2Cl2, À78 ꢀC to rt, 2 h; (d) LDA, HMPA, THF, À78 ꢀC, 20 min;
then dimethyl carbonate, THF, À78 ꢀC to 0 ꢀC, 30 min, 76% (2 steps);
(e) KHMDS, HMPA, THF, rt, 30 min; then 4a in THF, added to
previous mixture, 55 ꢀC, 18 h; (f) 2 N LiOH, THF:MeOH (3:1), 50 ꢀC,
18 h; then acetic acid followed by evaporation of volatiles, 80% (2
steps); (g) MMPP, CH2Cl2:MeOH (10:1), rt, 3 h, 92%; (h) TBAF,
THF, 65 ꢀC, 6 h, 85%; (i) TBAF, THF, 0 ꢀC, 30 min, 89%; (j) MnO2,
CH2Cl2, rt, 17 h, 98%; (k) MeMgCl, CH2Cl2, 0 ꢀC to rt, 15 min, 97%;
(l) CrO3, pyridine, celite, CH2Cl2, rt, 1 h, 40%.
All compounds were tested as enantiomeric mixtures
and compared to L-791,943 and ArifloTM, the most
advanced inhibitor in clinical development.15 Table 1
shows the effect of the substitution at various positions
by a methyl group on L-791,943. The potency to inhibit
PDE4 was preserved for compounds 7, 15, and 17.
Among these three compounds, compound 15 that
bears a methyl group at the position 3 on the pyridine-
N-oxide ring shows the best overall profile. As a mixture
of enantiomers, it showed improved pharmacokinetics
relative to L-791,943 in rats.
detail the effect of various functional groups. The 3-ethyl
analogue 16 was prepared as reported in Scheme 2. Some
polar substituents were also introduced. A primary alco-
hol substituent was attached to position 3 by preparing
the pyridylacetate 22 (Scheme 4). 3-Bromo-4-methylpyr-
idine was formylated at position 3 and, after reduction of
the aldehyde and protection of the primary alcohol, the
methyl group at carbon 4 was transformed to the corre-
sponding acetate. The pyridylacetate 22 was subjected
to the same sequence of reactions as described above in
Substitution at Position 3 on the Pyridine-N-oxide
Since position 3 on the pyridine-N-oxide ring was iden-
tified as a good site for substitution, we studied in more
Table 1. Biological data for methyl substituted L-791,943 analogues
Compd
R1 R2 R3 R4 R5 GST-PDE4A248 HWB (TNF-a)
IC50 (nM)
IC50 (mM)
L-791, 943
7
8
11
12
15
17
21
H
2-CH3
3-CH3
H
H
H
H
H
H
CH3
CH3
H
H
H
H
H
H
CH3
H
CH3
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
CH3
4.2
4.4
32
39
39
2.1
18
57
0.7
1.0
7.8
23
7.8
0.4
0.3
5.8
15
Scheme 3. Reagents and conditions: (a) SOBr2, pyridine, toluene, rt,
30 min, 57%; (b) LDA, THF, À78 ꢀC, 30 min; then methyl iodide,
À78 ꢀC to rt, 18 h, 66%; (c) Me4Sn, PdCl2(PPh3)2, toluene, reflux, 18
h, 33%; (d) LDA, HMPA, THF, À78 ꢀC, 30 min; then 18, THF,
À78 ꢀC, 3 h, 28%; (e) TBAF, THF, 65 ꢀC, 6 h; (f) MMPP, CH2Cl2:
MeOH (10:1), rt, 3 h, 77% (2 steps).
H
H
H
H
CDP-840
ArifloTM
4.2
38
18

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R. Frenette et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3009–3013
Table 2. Substitution on carbon 3 of the pyridine-N-oxide
the presence of the diarylchloride 4a to give the coupled
product 23. Oxidation of the pyridine followed by the
simultaneous cleavage of the SEM and the TIPS groups
with TBAF at 65 ꢀC afforded the primary alcohol 24.
The TIPS group of 23 was removed selectively without
cleaving the SEM group when treated with TBAF at
0 ꢀC. The alcohol produced was oxidized with MnO2 to
give an aldehyde, which, when subjected to methyl
Grignard addition followed by the cleavage of the SEM
ether and oxidation of the pyridine, gave the secondary
alcohol 25. The corresponding methyl ketone 26 was
obtained by oxidation with chronium (III) oxide.
Compd
R
GST-PDE4A248
IC50 (nM)
HWB (TNF-a)
IC50 (mM)
15
16
24
25
26
CH3
CH2CH3
CH2OH
CH(OH)CH3
COCH3
2.1
27
38
42
0.4
3.9
7.9
13
From Table 2, it is clear that increasing the size or the
polarity of the substituent at position 3, rapidly reduces
the potency on the PDE4 enzymes and in the HWB
assay. For example, the ethyl derivative 16 is about
10-fold less potent than the methyl analogue 15. The
substitution with a methyl group seems to be optimal.
2.7
2.9
Table 3. Enantiomers of 15
Since 15 is a mixture of enantiomers, we decided to resolve
it. Individual pure enantiomers were obtained, after an
efficient HPLC resolution on chiral column of the pyri-
dine precursor prior to the final oxidation step.16 The fast
eluting compound was identified as enantiomer 1 and the
slow eluting compound as enantiomer 2. Separated enan-
tiomers 1 and 2 were oxidized with MMPP to give
respectively L-826,141 and 27. Table 3 shows that the
PDE4 inhibitory activity resides predominantly in enan-
tiomer 1, with activities at least 10-fold superior to enan-
tiomer 2 and comparable to L-791,943 (see Table 1).
Compd
GST-PDE4A248
IC50 (nM)
HWB (TNF-a)
IC50 (mM)
15
L-826,141
27
rac. mixt.
enantiomer 1
enantiomer 2
2.1
1.3
23
0.4
0.3
3.7
In Vivo Studies
The pharmacokinetic profile of L-826,141 was then
evaluated, in comparison with L-791,943 in various
species. Table 4 shows that L-826,141 presents a shorter
half-life than L-791,943 in various species. The intro-
duction of a methyl group at position 3 on the pyridine-
N-oxide resulted in a diminished half-life while main-
taining the PDE4 inhibitory activity. For example, the
half-life observed in rats were >48 h and 10 h for L-
791,943 and L-826,141, respectively.
Table 4. Comparative in vivo profile of L-791,943 and L-826,141
L-791,943
L-826,141
Rat t1=2
Squirrel monkey t1=2
Dog t1=2
>48 h
>48 h
>48 h
10 h
36 h
19 h
8
58%
ð1 mg=kg; 4hÞ
0%
ð1 mg=kg; 0:5hÞ
ꢀꢀ
>
>
<
Efficacy in guinea pig
(dose ip, pre-treatment)
82%
ð1 mg=kg; 0:5hÞ
>
Compound L-826,141 is well absorbed in rat with a
bioavailability of 60% and a plasma level of 0.4 mM at 6
h when administered po at 3 mg/kg in 60% PEG200. Its
in vitro metabolism profile was investigated in human
and rat liver microsomal incubations performed under
previously described oxidative conditions.10 In the case
of L-791,943, the rate of metabolism was less than 20
pmol/mg protein*h with no detectable metabolites. For
L-826,141, the metabolic rates were 75 and 250 pmol/
mg protein*h in rat and human incubations, respec-
tively, with one metabolite being observed. The meta-
bolite was identified as the hydroxymethyl pyridinium
N-oxide by LC/MS analysis according to previously
described techniques.10 In rats, the metabolic rates
observed in vitro correlate with the half-lives, indicating
that the oxidative metabolism plays an important role in
the elimination of these compounds.
>
:
8
96%a
ð3 mg=kgÞ
ꢀꢀ
59%=100%
ð3 mg=kgÞ
33%=63%
ð1 mg=kgÞ
26%=38%
ð0:5 mg=kgÞ
>
>
>
>
>
>
<
Efficacy in squirrel monkey
early/late (dose po)
>
>
>
>
>
ꢀꢀ
>
:
Efficacy in sheep early/
late (dose iv)
85%/95%
(2 mg/kg)
62%/90%
(2 mg/kg)
Emesis in ferret (Cmax
)
>30 mg/kg
(14 mM)
>30 mg/kg
(10 mM)
aAnaesthetized squirrel monkey model (early-phase reported).

R. Frenette et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3009–3013
3013
Its in vivo efficacy was also demonstrated in the follow-
ing models. It inhibited ovalbumin-induced broncho-
constriction in conscious guinea pigs by 82% when
administered ip at 1 mg/kg (0.5 h pre-treatment).17 It
was also orally effective for the inhibition of broncho-
constriction induced by ascaris in conscious squirrel
monkey with 26–59% and 38–100% inhibition of the
early-phase and late-phase responses at doses varying
from 0.5 to 3 mg/kg, 4 h pre-treatment.18 Efficacy was
also demonstrated in the ascaris-induced bronchocon-
striction sheep model when administered iv at 2 mg/kg,
2 h pre-treatment.19 Furthermore, it does not induce
emesis in ferrets at 30 mg/kg po.
R. D.; Nieman, R. B.; Compton, C. H. Pulm. Pharmacol.
Ther. 1999, 12, 131.
7. Hanifin, J. M.; Chan, S. C.; Cheng, J. B.; Tofte, S. J.;
Henderson, W. R.; Kirby, D. S.; Weiner, E. S. J. Invest. Der-
matol. 1996, 107, 51.
8. Hughes, B.; Howat, D.; Lisle, H.; Holbrook, M.; James, T.;
Gozzard, N.; Blease, K.; Hughes, P.; Kingaby, R.; Warrellow,
G.; Alexander, R.; Eaton, M.; Perry, M.; Wales, M.; Smith,
B.; Owens, R.; Catterall, C.; Lumb, S.; Russel, A.; Allen, R.;
Merriman, M.; Bloxham, D.; Higgs, G. Br. J. Pharmacol.
1996, 118, 1192.
9. Harbinson, P. L.; MacLeod, D.; Hawksworth, R.; O’Toole,
S.; Sullivan, P. J.; Health, P.; Kilfeather, S.; Page, C. P.; Cost-
ello, J.; Holgate, S. T.; Lee, T. H. Eur. Respir. J. 1997, 10, 1008.
10. Li, C.; Chauret, N.; Trimble, L. A.; Nicoll-Griffith, D. A.;
Silva, J. M.; Macdonald, D.; Perrier, H.; Yergey, J.; Parton,
T.; Alexander, R. P.; Warrellow, G. J. Drug Metab. Dispo.
2001, 29, 232.
11. Guay, D.; Hamel, P.; Blouin, M.; Brideau, C.; Chan,
C. C.; Chauret, N.; Ducharme, Y.; Huang, Z.; Girard, M.;
Jones, T. R.; Laliberte, F.; Li, C.; Masson, P.; McAuliffe, M.;
Piechuta, H.; Silva, J.; Young, R. N.; Girard, Y. Bioorg. Med.
Chem. Lett. 2002, 12, 1457.
12. 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.
In conclusion, the introduction of a methyl group at
position 3 on the pyridine-N-oxide ring of L-791,943 led
to the identification of the PDE4 inhibitor L-826,141
which exhibits excellent in vitro activity. Furthermore, it
is well absorbed and presents a shorter half-life than L-
791,943 in a variety of animal species. Also, it is orally
active in the squirrel monkey model of antigen induced
bronchoconstriction (0.5–3 mg/kg) and is not emetic in
ferrets at a dose of 30 mg/kg.
13. Brideau, C.; Van Staden, C.; Sthyler, A.; Rodger, I. W.;
Chan, C. C. Br. J. Pharmacol. 1999, 126, 979.
14. Masatomo, I.; Tsukasa, K. J. Heterocycl. Chem. 1978, 15,
1425.
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