Substituted 2-pyridinemethanol derivatives as potent and selective phosphodiesterase-4 inhibitors

Article abstract of DOI:10.1016/S0960-894X(03)00314-7

The synthesis and the phosphodiesterase-4 (PDE4) inhibitory activity of 2-pyridinemethanol derivatives is described. The evaluation of the structure-activity relationship (SAR) in this series of novel PDE4 inhibitors led to the identification of compound

Full text of DOI:10.1016/S0960-894X(03)00314-7

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1923–1926
Substituted 2-Pyridinemethanol Derivatives as Potent and
Selective Phosphodiesterase-4 Inhibitors
Yves Ducharme,* Richard W. Friesen, Marc Blouin, Bernard Cote, Daniel Dube,
Diane Ethier, Richard Frenette, France Laliberte, Joseph A. Mancini, Paul Masson,
Angela Styhler, Robert N. Young and Yves Girard
´
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Quebec, Canada H9R 4P8
Received 29 October 2002; accepted 12 February 2003
Abstract—The synthesis and the phosphodiesterase-4 (PDE4) inhibitory activity of 2-pyridinemethanol derivatives is described. The
evaluation of the structure–activity relationship (SAR) in this series of novel PDE4 inhibitors led to the identification of compound
9 which exhibits excellent in vitro activity, desirable pharmacokinetic parameters and good efficacy in animal models of broncho-
constriction.
# 2003 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 The cAMP specific PDE4 iso-
zymes,2 encoded by four genes (A–D), are particularly
abundant in inflammatory and immune cells and in air-
way smooth muscles.3 It is now well established that
inhibition of PDE4 results in antiinflammatory and
immunomodulatory activities, both in vitro and in ani-
mal models.4 A number of PDE4 inhibitors are under
clinical evaluation for the treatment of asthma, chronic
obstructive pulmonary disease (COPD) and atopic der-
matitis.5 Despite promising results, the therapeutic
potential of PDE4 inhibitors remains hampered by their
dose-limiting side effects such as nausea and emesis.6
Therefore, the search for novel PDE4 inhibitors with
superior therapeutic index remains a very active field of
research.5,7
Recently, we reported how a SAR study directed
toward the improvement of the metabolic stability of
PDE4 inhibitor CDP8408 led to the discovery of com-
pound L-791,943.9 The development of L-791,943 was
precluded, despite an otherwise favorable pharmacolog-
ical profile, by an excessively long half-life in a variety
of animal species. The introduction of a soft metabolic
site10 to the structure of L-791,943 and the substitution
of
the
metabolically
resistant
bis(trifluoro-
methyl)carbinolbenzene moiety by an aminopyridine
residue11 both produced inhibitors with improved phar-
macokinetic profiles. We now report on the optimization
of a novel series of triarylethane derivatives of general
structure 1, bearing a 2-pyridinemethanol residue.12
The synthesis of PDE4 inhibitors 1 is presented in
Scheme 1. Palladium catalyzed methoxycarbonylation13
of bromopyridine 211 afforded in 95% yield the ester 3,
which was transformed to the Weinreb amide14 4.
Addition of a variety of organometallic reagents to this
intermediate gave access to ketones 5a–e. Selective
*Corresponding author. Tel.: +1-514-428-8621; fax: +1-514-428-
4900; e-mail: yves_ducharme@merck.com
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00314-7

1924
Y. Ducharme et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1923–1926
and tertiary alcohols 1f and 1g in yields of 35 and 50%
respectively. Benzyl derivative 8 was obtained by palla-
dium catalyzed coupling of bromopyridine 711 with
benzylmagnesium bromide in 73% yield (Scheme 3).
The compounds prepared were evaluated for their
potency to inhibit the PDE4A enzyme in vitro15 and for
their ability to inhibit LPS-induced TNF-a formation in
human whole blood (HWB).16 Initially, the effect of a
variety of substituents at position 2 of the pyridine ring
was evaluated (Table 1). Replacement of the methyl
group present in compound 6a by a lipophilic phenyl
group produces ketone 6b, an inhibitor showing a 4-fold
improvement in potency. The analogous secondary
alcohol 1f is even more potent, while the reduced benzyl
analogue 8 shows a decreased ability to inhibit LPS-
induced TNF-a formation in HWB. The favorable
effect brought by a hydroxyl group at this position is
confirmed by the fact that tertiary alcohol 1b is the most
potent inhibitor in this series with an IC50 of 0.6 nM in
the PDE4A assay and 0.35 mM in the HWB assay.
Next, the effect of substitution at the carbinol position
was investigated (Table 2). Reduction of lipophilicity
(methyl derivative 1a) has a negative effect on potency.
Non-aromatic analogues 1c and 1d are equipotent to
phenyl derivative 1b in the HWB assay despite lower
potencies in the enzyme assay. Replacement of the
phenyl group by heterocycles (e.g., thiazole 1e) did not
improve the inhibitory profile. The phenyl analogue 1b
remains the best PDE4 inhibitor in this series. Substitu-
tion of the methyl group (R2), at the carbinol position,
by larger alkyl (1g and 1h), trifluoromethyl (1i) or
phenyl (1j) units did not have significant effects on
potency (Table 3). Tertiary alcohol 1b was selected for
further evaluation.
Scheme 1. Reagents and conditions: (a) CO, CH3OH, Pd(OAc)2,
dppf, Et3N, DMF, 60 ꢀC, 95%; (b) CH3O(CH3)NHꢁ HCl, CH3MgBr,
THF, À78–0 ꢀC, 91%; (c) 5a: CH3MgBr, THF, 0 ꢀC, 100%; 5b:
PhMgCl, THF, À78–0 ꢀC; 5c: n-BuLi, THF, À78 ꢀC, 51%; 5d: cyclo-
hexylmagnesium chloride, THF, 0 ꢀC; 5e: thiazole, n-BuLi, THF,
À78 ꢀC, 98%; (d) MMPP, CH2Cl2/CH3OH (9/1), rt; (e) CH3MgBr,
CH2Cl2, À78 ꢀC, 50–80%.
oxidation of the monosubstituted pyridine ring was then
accomplished by treatment with magnesium mono-
peroxyphthalate (MMPP) to afford pyridine-N-oxides
6a–e. Addition of methylmagnesium bromide to these
ketones gave the desired tertiary alcohols 1a–e. Analo-
gues 1f–j were obtained by the addition of the requisite
organometallic reagents to phenylketone 6b (Scheme 2).
Use of ethylmagnesium bromide gave access to secondary
Pure diastereomers of inhibitor 1b were obtained in the
following way (Scheme 4). First, the enantiomers of
ketone 6b were resolved by chromatography, using a
Chiralpak AD HPLC column (25% i-PrOH in hex-
anes). Under these conditions, the PDE4 inhibitory
activity resides mainly in the fast-eluting enantiomer
(À)-6b (data not shown). Enantiomer (À)-6b was then
converted to 1b diastereomers 1 and 2 by treatment with
methylmagnesium bromide. A second chromatographic
separation on the Chiralpak AD HPLC column (25%
EtOH in hexanes) yielded the fast-eluting diastereomer
1 (9) and the slow-eluting diastereomer 2 (10). The same
procedure applied to enantiomer (+)-6b afforded
diastereomers 3 and 4 (11), which were not separated.
Scheme 2. Reagents and conditions: (a) 1f and 1g: EtMgBr, CH2Cl2,
À78 ꢀC, 35 and 50%; 1h: i-PrMgBr, CH2Cl2, À78 ꢀC, 47%; 1i:
TMSCF3/TBAF, THF, 0 ꢀC, 71%; 1j: PhMgCl, CH2Cl2, À78 ꢀC, 39%.
Scheme 3. Reagents and conditions: (a) BnMgBr, ZnBr2, Pd(PPh3)4,
THF, À78 ꢀC to rt, 73%.

Y. Ducharme et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1923–1926
Table 1. SAR at position 2 of the pyridine ring
Table 3. SAR on substituent R2 of the carbinol moiety
1925
Compd
X
PDE 4A
IC50 (nM)a
HWB (TNF-a)
IC50 (mM)a
Compd
R2
PDE 4A
IC50 (nM)a
HWB (TNF-a)
IC50 (mM)a
6a
102
23
6
2.2
0.60
0.36
0.77
0.35
16
1b
1g
1h
1i
CH3
Et
i-Pr
CF3
Ph
0.6
1.0
0.8
2.4
0.8
0.35
0.16
0.37
0.46
0.55
6b
1j
aEach IC50 value is an average of at least three experiments.
1f
8
3
1b
0.6
4
CDP840
—
aEach IC50 value is an average of at least three experiments.
Table 2. SAR on substituent R1 of the carbinol moiety
Scheme 4. Resolution of tertiary alcohol 1b.
Compd
R1
PDE 4A
IC50 (nM)a
HWB (TNF-a)
IC50 (mM)a
Table 4. Biological activity of diastereomers 9, 10 and 11
1b
0.6
0.35
Compd
PDE 4A
IC50 (nM)a
HWB (TNF-a)
IC50 (mM)a
1a
1c
CH3
n-Bu
40
6
0.89
0.34
1b
9
10
11
Racemic Mixture
Diastereomer 1
Diastereomer 2
0.6
2
1
48
0.35
0.16
0.11
3.5
1d
1e
1.2
6
0.30
0.49
Diastereomers 3 and 4
aEach IC50 value is an average of at least three experiments.
aEach IC50 value is an average of at least three experiments.
For example, inhibitors 9 and 10 inhibit ovalbumin
induced bronchoconstriction in conscious guinea pigs17
by 62 and 34% respectively when administered ip at 0.3
mg/kg (0.5 h pre-treatment). This behavior may corre-
late with the fact that diastereomer 9 presents a superior
pharmacokinetic profile in various animal species. For
this reason, compound 9 was selected for further eval-
uation. Inhibitor 9 is highly selective against the PDE4
enzyme (IC50=2 nM); no inhibitory activity was detec-
ted against other phosphodiesterases at concentrations
up to 5 mM. In contrast to its predecessor L-791,943,9
compound 9 presents suitable half-lives of 1.5 h in rats
and 2.2 h in squirrel monkeys following intravenous
administration at 5 mg/kg. The compound is also well
As observed previously in the triarylethane class of
PDE4 inhibitors,8,10,11 a major stereochemical effect on
inhibitory potency is observed at the chiral methine
carbon. Diastereomers 3 and 4 (11) are significantly less
potent than diastereomers 1 (9) and 2 (10) (Table 4). In
contrast, the stereochemistry at the chiral carbinol center
does not influence significantly the biological activity since
both diastereomers 9 and 10 are essentially equipotent in
vitro.
Despite similar intrinsic potencies, diastereomer 9 pre-
sents a slightly superior in vivo profile compared to 10.

1926
Y. Ducharme et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1923–1926
absorbed in both species, following oral dosage, with
bioavailabilities of 57 and 73% respectively. Induction
of emesis in squirrel monkeys is observed at an oral
dose of 10 mg/kg. Under these conditions, the maximal
concentration (Cmax) of 9 measured in plasma is 2.2 mM.
Knowing that compound 9 inhibits LPS-induced TNF-
a production in squirrel monkey whole blood with an
IC50 of 0.11 mM, an estimation of the emetic window
can be made by taking the ratio of these two con-
centrations. In the case of 9, this ratio is 20, while for
CDP840 and L-791,943 the same analysis provides
ratios of 8 and >20 respectively. Inhibitor 9 is also
effective for the inhibition of ascaris-induced broncho-
constriction in conscious sheep,18 exhibiting 33% and
91% inhibition of the early and late-phase responses
respectively, at a dose of 0.5 mg/kg iv (4 days of dosing)
given 2 h prior to challenge. On the whole, the data
indicates that inhibitor 9 shows good in vivo efficacy in
pulmonary function models while maintaining an
improved window with respect to emesis.
5. (a) Huang, Z.; Ducharme, Y.; MacDonald, D.; Robichaud,
A. Curr. Opin. Chem. Biol. 2001, 5, 432. (b) Dyke, H. J.;
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In conclusion, we have developed a novel series of
potent PDE4 inhibitors by replacing the metabolically
resistant bis(trifluoromethyl)carbinolbenzene moiety
found in L-791,943 by substituted 2-pyridinemethanol
residues. The results of the SAR study in this series led
to the identification of PDE4 inhibitor 9, which exhibits
excellent in vitro activity (HWB IC50=0.16 mM). Fur-
thermore, compound 9 is well absorbed and presents a
shorter half-life than L-791,943 in rats and squirrel
monkeys. Compound 9 is active in the guinea pig model
of ovalbumin-induced bronchoconstriction (0.3 mg/kg)
and in the sheep model of ascaris-induced bronchocon-
striction (0.5 mg/kg).
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S.; Bobechko, B.; Lario, P.; Bartlett, A.; Gorseth, E.; Gresser,
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