Racemic and chiral sulfoxides as potential prodrugs of the COX-2 inhibitors Vioxx and Arcoxia

Article abstract of DOI:10.1016/j.bmcl.2006.03.052

The preparation of the sulfoxide analogues 2 and 4, and their enantiomeric pure forms is discussed as well as their potential to act as prodrugs to the potent and selective sulfone-containing COX-2 inhibitors rofecoxib and etoricoxib. Sulfoxides 2 and 4 w

Full text of DOI:10.1016/j.bmcl.2006.03.052

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3209–3212
Racemic and chiral sulfoxides as potential prodrugs of the
COX-2 inhibitors VioxxÒ and ArcoxiaÒ
b
b
b
Francisco Caturla,a, Merce Amat, Raquel F. Reinoso, Monica Cordoba and
*
`
´
´
Graham Warrellowa
aDepartment of Medicinal Chemistry, Almirall Prodesfarma S.A., Research Center, Cardener 68-74, 08024 Barcelona, Spain
bDepartment of Biology, Almirall Prodesfarma S.A., Research Center, Cardener 68-74, 08024 Barcelona, Spain
Received 30 January 2006; revised 15 March 2006; accepted 16 March 2006
Available online 17 April 2006
Abstract—The preparation of the sulfoxide analogues 2 and 4, and their enantiomeric pure forms is discussed as well as their poten-
tial to act as prodrugs to the potent and selective sulfone-containing COX-2 inhibitors rofecoxib and etoricoxib. Sulfoxides 2 and 4
were shown to be effectively transformed in vivo into rofecoxib and etoricoxib, respectively, after oral administration in rats. In the
case of sulfoxide 2, both a slightly improved pharmacokinetic profile and a better pharmacological activity in an arthritis model were
seen when compared with rofecoxib.
Ó 2006 Elsevier Ltd. All rights reserved.
In a previous publication we disclosed the potential
advantages in the use of arylsulfoxides as prodrugs of
arylsulfones.1 Continuing our efforts in the design of
arylsulfoxides as potential prodrugs for the prototypical
sulfones found in the field of COX-2 inhibitors, we
selected the widely known drugs rofecoxib (VioxxÒ)
and etoricoxib (ArcoxiaÒ) in order to explore the prop-
erties of the corresponding racemic and enantiomeri-
cally pure sulfoxides.
case of rofecoxib, the potential sulfoxide prodrug 4-[4-
(methylsulfinyl)phenyl]-3-phenylfuran-2(5H)-one (2)
was prepared according to Scheme 1. The thioether 1
was synthesized by condensation of phenylacetic acid
with the bromoacetophenone 5. Using protocols previ-
ously described in these laboratories,1 the thioether 1
was oxidized in racemic fashion with NaIO4 (81%) or in
an enantioselective manner with (R,R)- or (S,S)-DET.
Based upon evidence accumulated from a previous publi-
cation,1 it was assumed in this study that the (R)-sulfoxide
was obtained when (R,R)-DET was used as chiral source,
while the use of (S,S)-DET provided the (S)-sulfoxide.
The enantiomeric excesses, as determined by capillary
electrophoresis (CE), were found to be 100% for the
(R)-sulfoxide and 93.4% for the (S)-sulfoxide.
Me
O
O
S
O
O
Cl
Me
N
S
O
In a similar fashion, the synthesis of the potential sulfox-
ide prodrug of etoricoxib, 2-pyridinyl-3-(4-methylsulfi-
nyl)phenylpyridine (4), was successfully accomplished
as outlined in Scheme 2. The key synthetic step in the
preparation of 4 was the selective palladium-catalyzed
cross-coupling reaction of the dichloropyridine 7 (pre-
pared from the known intermediate 63) employing the
pyridinyl stannane 83 as the organometallic partner.
O
N
Me
Rofecoxib
Etoricoxib
The synthetic strategy employed to prepare the sulfoxide
derivatives was based on the racemic or enantioselective
oxidation of the corresponding thioethers.2 Thus, in the
The thioether 3 was chemoselectively oxidized to the
racemic sulfoxide using NaIO4 (70%) (Scheme 2) or in
an enantioselective manner with (R,R)- or (S,S)-DET
(Scheme 3), obtaining in both cases the exclusive oxida-
Keywords: COX-2; Sulfoxides; Prodrugs.
*
Corresponding author. Present address: Treball 2-4, 08960 St. Just
Desvern, Spian. Tel.: +34 93 291 3583; fax: +34 93 312 8635; e-mail:
jfcaturl@almirall.es
1
tion of the sulfur atom according to the H NMR data.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.03.052

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F. Caturla et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3209–3212
O
O
O
O
Br
a
b
O
25%
81%
MeS
Me
S+
O
MeS
5
1
2
c or d
45-63%
O
O
O
O
Me
Me
S+
S+
O
O
(R)-2
(S)-2
Scheme 1. Reagents and conditions: (a) Phenylacetic acid, K2CO3, 18-crown-6, CH3CN; (b) NaIO4, MeOH–H2O (2:1); (c) Ti(OiPr)4/(R,R)-DET
(1:4), t-BuOOH, 1,2-DCE, À20 °C; (d) Ti(OiPr)4/(S,S)-DET (1:4), t-BuOOH, 1,2-DCE, À20 °C.
O
S+
SMe
Cl
Cl
N
O
N
N
Me
4
6
c
70%
a
47%
SMe
Me
SMe
Cl
Me3Sn
b
Cl
+
N
59%
N
Me
N
Cl
N
7
8
3
Scheme 2. Reagents: (a) i—TFA, ii—POCl3; (b) Pd(PPh3)4, NMP; (c) NaIO4, MeOH–H2O (2:1).
O
O
S+
S+
Me
Me
SMe
Cl
Cl
Cl
a or b
or
N
N
51-60%
N
N
Me
N
Me
N
Me
(S)-4
(R)-4
3
Scheme 3. Reagents and conditions: (a) Ti(OiPr)4/(R,R)-DET (1:4), t-BuOOH, 1,2-DCE, À20 °C; (b) Ti(OiPr)4/(S,S)-DET (1:4), t-BuOOH,
1,2-DCE, À20 °C.
The enantiomeric excesses, as determined by CE, were
found to be 100% for both the (R)-4 and the (S)-4
sulfoxides.
the sulfoxides except the (R)-4 enantiomer of etoricoxib
showed COX-2 activity in their own right. The selectiv-
ity ratio COX-1/COX-2 of all the sulfoxide prodrugs
tested was similar (Table 1).
All final compounds described herein were tested for
their ability to inhibit human COX-1 and COX-2 using
the whole blood assay described by Patrignani et al.4 All
Metabolic stability was found to be higher in human
than in rat microsomes for all the sulfoxides tested.

F. Caturla et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3209–3212
3211
Table 1. In vitro inhibitory activities against COX-2 and COX-1/
COX-2 selectivities in human whole blood
Table 3. Therapeutic activity
Compound Adjuvant arthritis
Pyresis % inhibition
Compound
COX-2 IC50 or % inhibition
(concentration (lM))
Selectivity ratio
COX-1/COX-2
% inhibition (dose) (mg/kg) (dose (mg/kg))
2
72% (0.3)
41% (0.3)
67% (1)
56% (1)
48% (1)
49% (3)
81% (3)
2
4.93
4.22
7
8
Rofecoxib
4
Etoricoxib
(R)-2
(S)-2
2.10
0.76
18
15
12
<2
22
122
60% (1)
Rofecoxib
4
Data are indicated as percentage of inhibition with dose (mg/kg) in
parentheses. Since SEM values never exceeded 15% of the media, they
have been omitted.
3.70
(R)-4
(S)-4
Etoricoxib
24.4 (10)
3.50
0.81
a therapeutic protocol. The test compounds were admin-
istered orally once daily for 7 days starting from day 14
after arthritis induction and paw edema was measured
24 h after the last administration. The rofecoxib prodrug
produced better effects than rofecoxib in both models
(Table 3).
These results suggest that the metabolism of these com-
pounds is mediated by an isoenzyme with species-depen-
dent activity. In each case, no significant differences in
the extent of metabolism were found between the
R- and S-enantiomers and the corresponding racemic
sulfoxide (Table 2). Data obtained from pooled human
liver microsomes showed that the sulfoxides studied
were converted mainly into the corresponding sulfones
(rofecoxib and etoricoxib) (data not shown).
rat, 1 mg/kg p.o.
600
2
Rofecoxib (2)
500
Rofecoxib
A comparison of the racemic sulfoxide 2 with the corre-
sponding sulfone (rofecoxib) shows that at both acidic
and neutral pH a marked increase in solubility is at-
tained going from sulfone to sulfoxide. Likewise, at neu-
tral pH the solubility of sulfoxide 4 was higher than that
of the corresponding sulfone (etoricoxib), while at acidic
pH both sulfoxide 4 and sulfone showed similarly good
solubility (Table 2).
400
300
200
100
0
0
1
2
3
4
5
6
Therapeutic activities were assessed for the racemic sulf-
oxides and the corresponding sulfones in the yeast-in-
duced pyresis model and the adjuvant-induced arthritis
model. The yeast-induced pyresis in a therapeutic proto-
col is an acute model. In this model, temperature mea-
surements were taken at 1 h intervals from 1 to 5 h
after single oral administration of the compounds. As a
chronic model of inflammation the compounds were test-
ed in the adjuvant-induced arthritis in male Wistar rats in
Time (h)
Figure 1. Plasma concentrations of sulfoxide 2 (prodrug) and sulfone
rofecoxib (drug) after oral administration of prodrug or drug at 1 mg/
kg to male Wistar rats as a suspension of 0.5% methylcellulose and
0.1% Tween 80. Each data point represents the mean SD of two to
three values.
Rat, 1 mg/kg p.o.
Table 2. In vitro metabolism and thermodynamic solubility of
sulfoxides (2 and 4) and the corresponding sulfones (etoricoxib and
rofecoxib)
700
4
Etoricoxib (4)
Etoricoxib
600
500
400
300
200
100
0
Compound
Microsome
metabolisma
(%)
Thermodynamic solubilityb
(lg/ml)
Human Rat SGFc (pH 1.8) PBSd (pH 7.2)
2
5
35
49
40
38
21
26
17
6
717
—
537
—
(R)-2
(S)-2
1
4
—
16
—
15
Rofecoxib
4
—
6
>1000
—
—
>1000
—
—
(R)-4
(S)-4
Etoricoxib
5
2
0
1
2
3
4
5
6
4
>1000
104
Time (h)
a Assay conditions: metabolism (1 mg/mL microsomal protein, 5 lM
compound, 30 min, and 37 °C incubation).
Figure 2. Plasma concentrations of sulfoxide 4 (prodrug) and sulfone
etoricoxib (drug) after oral administration of prodrug or drug at 1 mg/
kg to male Wistar rats as a suspension of 0.5% methylcellulose and
0.1% Tween 80. Each data point represents the mean SD of three
values.
b Thermodynamic solubility for crystalline compound (Target con-
centration: 1 mg/ml, 24 h, and 37 °C incubation).
c SGF, simulated gastric fluid.
d PBS, phosphate-buffered saline.

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F. Caturla et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3209–3212
Table 4. Pharmacokinetic parameters following prodrug (2, 4) and parent drug (etoricoxib, rofecoxib) administration to male Wistar rats
Parameter
2
Rofecoxib
4
Etoricoxib
2
Rofecoxib
4
Etoricoxib
Cmax (ng/ml)
tmax (h)
AUC0-t (ng h/ml)
334
0.3
468
0.4
237 (34)
0.4 (0.1)
531 (234)
133 (33)
0.6 (0.4)
578 (96)
254 (98)
0.3 (0.0)
803 (117)
427 (191)
0.3 (0.0)
1656 (497)
318
979
Results expressed as means (n = 2–3) and SD (between brackets). Assay conditions: pharmacokinetic parameters of prodrug or parent drugs
following single oral administration of 1 mg/kg to male Wistar rats as a suspension of 0.5% methylcellulose and 0.1% Tween 80.
Following oral administration of 1 mg/kg to male Wis-
tar rats, the sulfoxides were well absorbed and rapidly
converted into their sulfones (Figs. 1 and 2). The sul-
fone-to-sulfoxide AUC ratio was greater for the
rofecoxib prodrug than for the etoricoxib prodrug (3.1
vs 1.4 for prodrugs 2 and 4, respectively) (Table 4).
Thus, after rofecoxib prodrug administration (i.e.,
sulfoxide 2), both the Cmax and AUC of rofecoxib were
greater than those observed after direct administration
of rofecoxib itself, while the opposite was observed in
the case of etoricoxib (Table 4, Figs. 1 and 2).
an improvement of the pharmacokinetic and the phar-
macodynamic properties of etoricoxib itself.
References and notes
1. Caturla, F.; Amat, M.; Reinoso, R. F.; Calaf, E.; Warrel-
low, G. Bioorg. Med. Chem. Lett. 2006, in press.
2. (a) Caturla Javaloyes, J. F.; Warrellow, G. WO Patent
04072057, 2004; (b) Caturla Javaloyes, J. F.; Warrellow, G.
WO Patent 04072037, 2004.
3. (a) Friesen, R. W.; Brideau, C.; Chan, C. C.; Charleson, S.;
ˆ
´
Deschenes, D.; Dube, D.; Ethier, D.; Fortin, R.; Gauthier,
J. Y.; Girard, Y.; Gordon, R.; Greig, G. M.; Riendeau, D.;
Savoie, C.; Wang, Z.; Wong, E.; Visco, D.; Xu, L. J.;
Young, R. N. Bioorg. Med. Chem. Lett. 1998, 8, 2777; (b)
Dube, D.; Fortin, R.; Friesen, R.; Wang, Z.; Gauthier, J.Y.
WO Patent 9803484, 1998.
In conclusion, the sulfoxide-based rofecoxib prodrug 2,
when compared with rofecoxib itself, led to improved
pharmacokinetic levels of circulating rofecoxib after
oral administration. As such, the rofecoxib prodrug
gave a better pharmacological response in in vivo mod-
els. These effects are likely due to a marked increase in
solubility of the sulfoxide over the sulfone. On the other
hand, the observed increase in solubility of the sulfox-
ide-based etoricoxib prodrug 4 did not translate into
4. Patrignani, P.; Panara, M. R.; Greco, A.; Fusco, O.; Natoli,
`
C.; Iacobelli, S.; Chipollone, F.; Ganci, A.; Creminon, C.;
Maclouf, J.; Patrono, C. J. Pharmacol. Exp. Ther. 1994,
271, 1705.