3-[4-(Methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl) phenyl ketone as a potent and orally active cyclooxygenase-2 selective inhibitor: Synthesis and biological evaluation

Article abstract of DOI:10.1021/jm0582064

Incorporation of a spacer group between the central scaffold and the aryl ring resulted in a new cyclooxygenase-2 (COX-2) selective inhibitor core structure, 3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl) phenyl ketone (20), with COX-2 IC

Full text of DOI:10.1021/jm0582064

3930
J. Med. Chem. 2005, 48, 3930-3934
Brief Articles
3-[4-(Methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl) Phenyl Ketone as a
Potent and Orally Active Cyclooxygenase-2 Selective Inhibitor: Synthesis and
Biological Evaluation
Subhash P. Khanapure,* Michael E. Augustyniak, Richard A. Earl, David S. Garvey, L. Gordon Letts,
Allison M. Martino, Madhavi G. Murty, David J. Schwalb, Matthew J. Shumway, Andrzej M. Trocha,
Delano V. Young, Irina S. Zemtseva, and David R. Janero
NitroMed, Inc., 125 Spring Street, Lexington, Massachusetts 02421
Received March 9, 2005
Incorporation of a spacer group between the central scaffold and the aryl ring resulted in a
new cyclooxygenase-2 (COX-2) selective inhibitor core structure, 3-[4-(methylsulfonyl)phenyl]-
5-(trifluoromethyl)(2-pyridyl) phenyl ketone (20), with COX-2 IC50 ) 0.25 µM and COX-1 IC50
) 14 µM (human whole blood assay). Compound 20 was orally active in the rat air pouch model
of inflammation, inhibiting white blood cell infiltration and COX-2-derived PG production. Our
data support the identification of a novel COX-2 selective inhibitor core structure exemplified
by 20.
Introduction
One mammalian cyclooxygenase (COX) isozyme, COX-
1, is constitutively present in platelets and all tissues
and produces prostaglandins (PGs) with homeostatic
functions including gastric mucosal cytoprotection, renal
blood flow regulation, and vascular antithrombotic
activity. Although constitutive in a few tissues, COX-2
isozyme is transiently induced by proinflammatory
stimuli to generate PGs that mediate the inflammatory
response.1 As inhibitors of COX isozymes, traditional
nonsteroidal antiinflammatory drugs (NSAIDs) relieve
the signs and symptoms of inflammation by decreasing
PG production but may cause serious gastrointestinal
(GI) and renal damage, especially with long-term use.1,2
By reduction of PG synthesis at sites of inflammation,
COX-2 selective inhibitors have been clinically validated
as antiinflammatory therapeutics for indications such
Figure 1.
as rheumatoid arthritis.3-5 Enhanced GI safety is the
major clinical advantage of COX-2 selective inhibitors
a central scaffold, etoricoxib validated the importance
over traditional NSAIDs.6,7 Prior to completion of this
of pyridyl analogues as COX-2 selective antiinflamma-
work, three COX-2 selective inhibitors were marketed
tory therapeutics. Lumiracoxib (5) is a new COX-2
selective inhibitor that is structurally and pharmaco-
logically distinctive (Figure 1). Although it contains an
in the U.S.: celecoxib (1),8 rofecoxib (2),9 and valdecoxib
(3)10 (Figure 1). Rofecoxib (Vioxx) was recently with-
drawn11 worldwide because of evidence of increased
acid group similar to classical nonselective NSAIDs,
cardiovascular risk in select, high-dose patients that
lumiracoxib still shows superior GI tolerance, suggest-
may reflect rofecoxib’s greater COX-2 selectivity.12 The
ing that PG synthesis inhibition is more critical to
NSAID-induced GI toxicity than an acidic drug-mu-
moderately COX-2 selective inhibitor celecoxib has not
shown similar adverse cardiovascular effects,13 but
cosal interaction. In phase III clinical trials, the GI
valdecoxib, with greater COX-2 selectivity, has.12 Cele-
tolerability of lumiracoxib is superior to that of ibupro-
coxib and valdecoxib are comparable to conventional
fen and equivalent to that of celecoxib and rofecoxib.16,17
NSAIDs in terms of analgesic, antipyretic and antiin-
The nonabsolute GI safety of extant COX-2 selective
flammatory activity.8,10
antiinflammatory agents and their pharmacological and
side effect limitations invite improvement and develop-
ment of new core inhibitor structures. We recently
The COX-2 selective inhibitor etoricoxib (4)14,15 is an
approved drug in Europe. Containing a pyridyl ring as
described a new series of metharyl COX-2 selective
inhibitors and showed that a spacer group between the
* To whom correspondence should be addressed. Phone: 781-266-
4111. Fax: 781-274-8083. E-mail: skhanapure@nitromed.com.
10.1021/jm0582064 CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/07/2005

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 11 3931
Scheme 1
This lack of oral in vivo antiinflammatory activity by
COX-2 selective inhibitor 6 presumably reflected poor
absorption, distribution, metabolism, and excretion
properties and prompted us to explore the pyridyl ring
as the central scaffold in view of the enhanced bioavail-
ability it can afford because of salt formation in GI
tract.14,15 Recently, pyridinic nimesulide analogues were
found to be preferential COX-2 selective inhibitors with
antiinflammatory properties similar to those of nime-
sulide in vivo.19 Herein, we report that 3-[4-(methylsul-
fonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl) phenyl ke-
tone (20) is a potent COX-2 selective inhibitor. Synthesis
and biological evaluation of this compound are pre-
sented.20
Chemistry
We initially investigated the pyridyl analogue 12 to
determine whether incorporating a carbonyl spacer
group between the central pyridyl ring and the aryl ring
might lead to a potent COX-2 inhibitor. The general
synthesis of 3-fluorophenyl 2-[4-(methylsulfonyl)phenyl]-
(3-pyridyl) ketone (12) is illustrated in Scheme 1. 2-[4-
(Methylsulfonyl)phenyl](3-pyridyl) 2-pyridyl ketone (15)
was prepared using a similar synthetic pathway as
described in Scheme 1 but starting from 2-chloro(3-
pyridyl) 2-pyridyl ketone (13) (Scheme 2).
Scheme 2
Our initial route to 12 (Scheme 1) did not allow the
installation of the 4-sulfonylphenyl COX-2 pharmaco-
phore at the 3-position and a metharyl group at the
2-position of the central pyridine ring because of the lack
of a suitably substituted commercial starting material.
Therefore, the synthesis was modified to incorporate a
nitrile functionality in the spacer group that could be
converted to a ketone by oxidative decyanation,21 as
shown in Scheme 3a. Alternatively, the nitrile group in
16 was converted into ketone 21 prior to the Suzuki-
Miyaura coupling (Scheme 3b). Reaction of 16 with
aryl ring and the central benzo-1,3-dioxolane ring
(scaffold) significantly increased COX-2 inhibitory po-
tency.18 Within this metharyl series, 6 was identified
as a potent COX-2 selective inhibitor in vitro [COX-2
IC50 ) 1.0 µM and COX-1 IC50 ) 20 µM in human whole
blood (HWB)] that inhibited COX-2-driven PGE2 pro-
duction when administered in vivo directly at the site
of inflammation in a rat air pouch model but not when
administered orally.
Scheme 3

3932 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 11
Table 1. IC50 Valuesa of Select COX-2 Inhibitors in HWB
Brief Articles
Table 2. Oral Antiinflammatory Potency of 20 in the Rat Air
Pouch Modela
COX-1
COX-2
COX-2/COX-1
selectivity
compd
20
etoricoxib
celecoxib
rofecoxib
IC50 (µM)
IC50 (µM)
oral dose
% inhibition
% inhibition
of PGE2
compd
mg/kg (mmol) of WBC infiltration
14
>200
14
0.25
2
1.2
0.5
56
>100
11
20
etoricoxib
a n ) 11 rats.
6.1 (15)
5.4 (15)
46.2 ( 3.05
45 ( 6.7
58.9 ( 5.0
61 ( 6.7
62
124
a Average of two blood donors.
To our knowledge, 20 is the most potent COX-2
inhibitor in the HWB COX assay yet reported. Thus,
20 represents a COX-2 selective inhibitor in a novel
chemical series for this drug class. It is not, however,
the most selective, which would increase its attractive-
ness as a therapeutic were the hypothesis to be proven
that the cardiovascular liability of certain COX-2 inhibi-
tors reflects their very high selectivity for this COX
isozyme.12
In Vivo Antiinflammatory Activity. Rat Air
Pouch Model. We evaluated 20 in vivo in the rat
carrageenan-induced air pouch inflammation model, a
standard and reliable model for COX-2 inhibitor phar-
macological profiling and, more specifically, assessment
of in vivo COX-2 driven PGE2 production.10,18 In this
model, 20 showed good oral activity with 59% inhibition
of PGE2 formation and 46% inhibition of white blood
cell (WBC) infiltration at a 15 µmol/kg dose, a profile
similar to that of etoricoxib (Table 2).
boronic acid 10 under classical Pd(PPh3)4-mediated
cross-coupling reaction conditions failed to yield the
desired product 17. The reaction of 21 and 22 using Pd-
(dba)2/P(t-Bu)3 and cesium carbonate as base in dioxane
gave 20 in 39% yield. Our recently developed method22
for the optimized Suzuki-Miyaura cross-coupling of less
reactive heteroaryl chlorides and arylboronic acids using
an air-stable palladium phosphinous acid complex [(t-
Bu)2P(OH)]2PdCl2 (POPd) as a catalyst was found to be
very effective and convenient for the Pd-catalyzed
coupling of 21 and 22 to give the desired product 20 in
very high yield (88%) (Scheme 3b).
Results and Discussion
In Vitro Studies. Compounds were initially evalu-
ated in a standard HWB assay for their ability to inhibit
COX-1 at 100 µM and COX-2 at 10 and 1 µM (table in
Supporting Information). Compounds that showed good
COX-2 inhibition at 10 µM were also evaluated for their
COX-2 and COX-1 IC50 values to index COX-2 selectiv-
ity. Standard COX-2 inhibitors were evaluated in paral-
lel (Table 1).
Compound 12, in which a 3-fluorophenyl group was
linked by a carbonyl spacer at the 3-position, was
initially screened for COX-2 inhibitory activity in hu-
man whole blood (table in Supporting Information). It
was moderately active (55% inhibition of COX-2 at 10
µM). We next explored the effect of an additional pyridyl
moiety by replacing the aryl ring at position 3 of central
pyridine scaffold to increase the hydrophilicity of the
molecule. Increased aqueous solubility often improves
compound absorption, bioavailability, and in vivo po-
tency.14 But the 2-pyridyl derivative 15 exhibited poor
COX-2 inhibitory activity (table in Supporting Informa-
tion).
Conclusion
We have discovered a novel compound 20 that is a
very potent COX-2 selective inhibitor with appreciable
in vivo antiinflammatory activity.
Experimental Section
For general comments, see our earlier publication in this
series.18 2-Chloro(3-pyridyl) 2-pyridyl ketone (9) and 2-[3-
chloro-5-(trifluoromethyl)(2-pyridyl)]-2-phenylethanenitrile (16)
were purchased from Ryan Scientific, Inc., SC.
COX-1 and COX-2 Enzyme Assay in HWB. The assay
for COX-1 and COX-2 enzyme activity in HWB was performed
essentially as described by Young et al.25 and as we have
previously described.18
Rat Air Pouch Inflammation Model. An air pouch
inflammation model was established in male Sprague Dawley
(SD) rats (200-250 g, Charles River Laboratories) previously
detailed.18 Upon pouch development on day 6, vehicle or test
compound in 0.5% methyl cellulose was administered by oral
gavage. One hour later, inflammation was induced by injecting
1 mL of 1% carrageenan into the air pouch. Three hours after
carrageenan injection, the rats were sacrificed and the pouch
exudates were collected. Exudate white blood cells were
quantified by automated counting, and exudate PGE2 was
determined by enzyme immunoassay (Cayman).
General Procedures. Suzuki-Miyaura Coupling Re-
action: Method A. The chloropyridyl compound (5 mmol) and
the corresponding benzeneboronic acid (5 mmol) were dissolved
in toluene (50 mL), and sodium carbonate (2 M, 5 mL, 10
mmol) was added. To this reaction mixture was added ethanol
(20 mL) followed by tetrakis(triphenylphosphine)palladium
(0.34 g, 0.25 mmol). The reaction mixture was refluxed
overnight under a nitrogen atmosphere and then diluted with
water (25 mL). The organic layer was separated, and the
aqueous layer was extracted with EtOAc (2 × 75 mL). The
combined organic extracts were washed with water (2 × 50
mL) and brine (1 × 50 mL), dried over sodium sulfate, and
filtered. The filtrate was evaporated under reduced pressure
to give the crude product. The product was purified by
trituration with ethyl acetate/hexane or by chromatography
Compound 20, in which a phenyl substituent is linked
to the central pyridyl ring by a carbonyl spacer, was a
potent, highly selective COX-2 inhibitor (COX-2 IC50
)
0.25 µM and COX-1 IC50 ) 14 µM in HWB). Thus, our
earlier finding in the metharyl series of compounds that
the spacer group was critical for optimizing COX-2
inhibition18 was equally applicable to the pyridyl-
metharyl compound 20. The spacer group presumably
increases flexibility to allow for attainment of a molec-
ular conformation that enahnces inhibitor interaction
with the COX-2 active site. Additionally, the trifluoro-
methyl group on the pyridine ring may have contributed
to the improved activity of 20. A trifluoromethyl group
on the central ring of the celecoxib is essential for COX-2
activity; it acts as an acceptor to form a hydrogen bond
with the NH group of arginine-120.23 Elimination of the
trifluoromethyl group of celecoxib dramatically de-
creased COX-2 inhibitory activity because of a change
in disolvation energy and loss of van der Waals interac-
tion with COX.24

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 11 3933
on silica gel and elution with hexanes/EtOAc (8:2 to 6:4) to
give the title compound as a white solid.
sure, and the residue extracted with ethyl acetate (2 × 50 mL).
The combined extracts were washed with water (2 × 50 mL)
and brine (1 × 25 mL), dried over sodium sulfate, and filtered,
and the solvent was evaporated at reduced pressure to give
the crude product. Purification by column chromatography
over silica gel using gradient 20-40% ethyl acetate in hexane
gave the less polar compound as a white crystalline product
(20) (85 mg), mp 141-142 °C. 1H NMR (CDCl3) δ 9.03 (s, 1
H), 8.14 (d, J ) 1.3 Hz, 1 H), 7.96 (d, J ) 8.3 Hz, 1 H), 7.85
(dd, J ) 7.2 and 1.0 Hz, 1 H), 7.66 (t, J ) 7.6 Hz, 1 H), 7.58 (d,
J ) 8.3 Hz, 2 H), 7.51 (t, J ) 7.5 Hz, 2 H), 3.03 (s, 3 H); 13C
NMR (CDCl3) δ 193.1, 158.2, 145.05, 141.5, 140.7, 135.3, 134.3,
130.3 (2 x C), 129.7 (2 C), 128.2 (2 C), 127.8, (2 C), 127 0 (q, J
) 33 Hz, CF3), 124.6, 121.0, 44.3; LRMS (APIMS) m/z 406 (M
+ H)+. From the more polar fractions, 490 mg of 2-{3-[4-
(methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl)}-2-phe-
nylethanenitrile (19) was isolated as a light-yellow solid, mp
Oxone Oxidation Reaction: Method B. The thiomethyl
compound (4 mmol) was dissolved in methanol (60 mL) with
stirring at room temperature. A solution of oxone (8 mmol) in
water (20 mL) was added. The reaction mixture was stirred
at room temperature for 2 h. The solvent methanol was
evaporated at reduced pressure, and the remainder was
diluted with water (25 mL), neutralized with ammonium
hydroxide, and extracted with EtOAc (2 × 50 mL). The
combined organic extracts were washed with water (2 × 50
mL) and brine (1 × 25 mL), dried over sodium sulfate, and
filtered. The filtrate was evaporated under reduced pressure,
and the product was purified by trituration with ethyl acetate/
hexane or by chromatography on silica gel and elution with
hexanes/EtOAc (19:1) to give the desired methylsulfonyl
compound as a white solid in excellent yield.
Suzuki-Miyaura Coupling Reaction Using POPd Cata-
lyst: Method C. To a solution of chloropyridine (2 mmol) in
DME (8 mL) was added boronic acid (10) (500 mg, 2.5 mmol)
followed by Cs2CO3 (5 mmol) and POPd (25 mg, 0.05 mmol,
0.02 mol %). The reaction mixture was refluxed overnight and
then cooled to room temperature and filtered. The filtrate was
evaporated at reduced pressure, and the residue was extracted
with ethyl acetate, washed with aqueous saturated Na2CO3,
water, and brine, and dried. The solvent was evaporated and
the residue obtained was purified by trituration with ethyl
acetate/hexane or by chromatography on silica gel and elution
with hexanes/EtOAc (6:4) to give the desired methylsulfonyl
compound as a white solid in excellent yield.
1
78 °C. H NMR (CDCl3) δ 9.05 (s, 1 H), 8.1 (d, J ) 1.6 Hz, 1
H), 7.46 (d, J ) 8.2 Hz, 2 H), 7.33 (m, 1 H), 7.16 (m, 2 H), 5.42
(s, 1 H), 3.18 (s, 3 H); 13C NMR (CDCl3) δ 155.0, 146.6, 141.6,
141.4, 135.5, 135.1, 133.6, 130.1 (2 x C), 129.2 (2 C), 128.1,
127.8, (2 C), 127.0 (2 C), 126.3 (q, J ) 33 Hz, CF3), 124.6, 121.0,
118.1, 44.4, 42.3; LRMS (APIMS) m/z 417 (M + H)+.
Oxidative Decyanation of Compound 19 To Give 20.
Nitrile 19 (208 mg, 0.5 mmol) was dissolved in anhydrous THF
(4 mL). The solution was cooled to -78 °C, and under nitrogen
atmosphere 0.5 M potassium bishexamethylsilazide (1.1 mL)
was added slowly. The solution turned dark-red and was
further stirred at -78 °C for 15 min and then slowly allowed
to warm to 0 °C over a period of 1 h. Then air was bubbled
through the solution for 1 h at room temperature, and then
the reaction flask was left open to air overnight. Product was
extracted with dichloromethane, and the usual workup gave
the crude product that was purified by column chromatography
over silica gel using 20% ethyl acetate in hexane to give the
pure product 20, 110 mg in 54% yield. The spectral data were
identical to the spectral data of the product obtained by method
C as described above.
3-Chloro-5-(trifluoromethyl)(2-pyridyl) Phenyl Ketone
(21). Nitrile 16 (4 g, 13.48 mmol) was dissolved in anhydrous
THF (25 mL). The solution was cooled to -78 °C, and under
nitrogen atmosphere 0.5 M potassium bishexamethylsilazide
(27 mL) was added slowly. The solution was further stirred
at -78 °C for 15 min and then slowly allowed to warm to 0 °C
over a period of 1 h. Then dry air was bubbled through the
solution for 1 h at room temperature while allowing it to warm
to room temperature. Product was extracted with ethyl acetate,
and the usual workup gave the crude product that was purified
by column chromatography over silica gel using 10% ethyl
acetate in hexane to give the pure product ketone 21 (3.8 g in
98% yield) as a white solid, mp 58 °C. 1H NMR (CDCl3) δ 8.84
(s, 1 H), 8.09 (s, 1 H), 8.09 (d, J ) 7.4, 2 H), 7.64 (t, J ) 7.3
Hz, 1 H), 7.49 (t, J ) 7.6 Hz, 2 H); 13C NMR (CDCl3) δ 191.3,
157.7, 143.9, 143.8, 135.1, 134.5, 130.2 (2 C), 129.7, 128.8 (2
C), 128.3 (d, JC-F ) 33.75 Hz), 122.27 (q, JC-F ) 271 Hz, CF3);
LRMS (APIMS) m/z 286 (M + H)+, 288 [(M + H) + 2]+.
3-[4-(Methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-py-
ridyl) Phenyl Ketone (20). Compound 20 was prepared,
using method C, in 88% yield as a colorless crystalline solid,
mp 141-142 °C. 1H NMR (CDCl3) δ 9.03 (s, 1 H), 8.14 (d, J )
1.3 Hz, 1 H), 7.96 (d, J ) 8.3 Hz, 1 H), 7.85 (dd, J ) 7.2 and
1.0 Hz, 1 H), 7.66 (t, J ) 7.6 Hz, 1 H), 7.58 (d, J ) 8.3 Hz, 2
H), 7.51 (t, J ) 7.5 Hz, 2 H), 3.03 (s, 3 H); 13C NMR (CDCl3)
δ 193.1, 158.2, 145.05, 141.5, 140.7, 135.3, 134.3, 130.3 (2 C),
129.7 (2 C), 128.2 (2 C), 127.8, (2 C), 127 0 (q, J ) 33 Hz, CF3),
124.6, 121.0, 44.3; LRMS (APIMS) m/z 406 (M + H)+.
Procedure Using Pd2(dba)3/P(Ph3)4 Catalyst: 3-[4-
(Methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl)
Phenyl Ketone (20) and 2-{3-[4-(Methylsulfonyl)phenyl]-
5-(trifluoromethyl)(2-pyridyl)}-2-phenylethanenitrile (19).
2-[3-Chloro-5-(trifluoromethyl)(2-pyridyl)]-2-phenylethaneni-
trile (16) (4.8 g, 16.17 mmol) and 4-(methylthio)benzeneboronic
acid (10) (4.15 g, 25 mmol) were dissolved in anhydrous
dioxane (80 mL). To this reaction mixture were added succes-
sively tris(dibenzylideneacetone)dipalladium(0) (0.58 g, 0.633
mmol), tri-tert-butylphosphine (150 mg, 0.724 mmol), and
cesium carbonate (6.5 g, 20 mmol), and the mixture was
refluxed overnight under nitrogen atmosphere. Reaction was
monitored by thin-layer chromatography, which indicated the
starting material and the product. Additional 4-(methylthio)-
benzeneboronic acid (10) (4.15 g, 25 mmol), tris(dibenzylide-
neacetone)dipalladium(0) (0.58 g, 0.633 mmol), tri-tert-bu-
tylphosphine (150 mg, 0.724 mmol), and base cesium carbonate
(6.5 g, 20 mmol) were added, and the mixture was further
refluxed for another 24 h. The mixture was then cooled to room
temperature, and solvent was evaporated at reduced pressure.
The residue was treated with water and extracted with ethyl
acetate (1 × 250 mL). The combined extracts were washed with
water (4 × 250 mL) and brine (1 × 250 mL), dried over sodium
sulfate, treated with charcoal, filtered, and concentrated at
reduced pressure to give the crude product. Purification by
column chromatography over silica gel using 5% ethyl acetate
in hexane gave 1.3 g of thick oil that was a mixture (85:15) of
2-[3-(4-methylthiophenyl)-5-(trifluoromethyl)(2-pyridyl)]-2-phen-
ylethanenitrile (17) and 3-(4-methylthiophenyl)-5-(trifluoro-
methyl)(2-pyridyl) phenyl ketone (18). This mixture was
dissolved in methanol (60 mL). OXONE (4.35 g, 7.1 mmol) in
water (15 mL) was added, and the mixture was stirred at room
temperature for 1.5 h. It was then neutralized with ammonium
hydroxide, solvent methanol was evaporated at reduced pres-
Supporting Information Available: COX-2 and COX-1
percentage inhibition in HWB, elemental analysis data, ex-
perimental procedures, and spectroscopic data for 9, 11, 12,
14, and 15. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) For a recent review, see: Khanapure, S. P.; Letts, L. G.
Perspectives and clinical significance of the biochemical and
molecular pharmacology of eicosanoids. The Eicosanoids; John
Wiley & Sons: London, 2004; pp 131-162.
(2) Gajaraj, N. M. Cyclooxygenase-2 inhibitors. Anesth. Analg. 2003,
96, 1720-1738.
(3) Turini, M. E.; DuBois, R. N. Cyclooxygenase-2: A therapeutic
target. Annu. Rev. Med. 2002, 53, 35-57.
(4) Vane, J. R.; Botting, R. M. Therapeutic Roles of Selective COX-2
Inhibitors; William Harvey Press: London, 2001; pp 1-548.

3934 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 11
Brief Articles
(5) Rodrigues, C. R.; Veloso, M. P.; Verli, H.; Fraga, C. A.; Miranda,
A. L.; Barreiro, E. J. Selective PGHS-2 inhibitors: A rational
approach for the treatment of the inflammation. Curr. Med.
Chem. 2002, 9, 849-867.
(6) Bombardier, C.; Laine, L.; Reicin, A.; Shapiro, D.; Burgos-Vargas,
R.; Davies, B.; Day, R.; Ferraz, M. B.; Hawkey, C. J.; Hochberg,
M. C.; Kvien, T. K.; Schnitzer, T. J. Comparison of upper
gastrointestinal toxicity of rofecoxib and naproxen in patients
with rheumatoid arthritis. N. Engl. J. Med. 2000, 343, 1520-
1528.
(7) Silverstein, F. E.; Faich, G.; Goldstein, J. L.; Simon, L. S.; Pincus,
T.; Whelton, A.; Makuch, R.; Eisen, G.; Agrawal, N. M.; Stenson,
F. W.; Burr, A. M.; Zhao, W. W.; Kent, J. D.; Lefkwith, J. B.;
Verburg, K. M.; Geis, G. S. GI toxicity with celecoxib vs NSAIDs
for arthritis. JAMA, J. Am. Med. Assoc. 2000, 284, 1247-1255.
(8) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J.
W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.;
Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.;
Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.;
Zhang, Y. Y.; Isakson, P. C. Synthesis and biological evaluation
of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors:
identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-
pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib). J. Med.
Chem. 1997, 40, 1347-1365.
with other agents that selectively inhibit cyclooxygenase-2. J.
Pharmacol. Exp. Ther. 2001, 296, 558-566.
(15) Davies, I. W.; Marcoux, J.-F.; Corley, E. G.; Journet, M.; Cai,
D.-W.; Palucki, M.; Wu, J.; Larsen, R. D.; Rossen, K.; Pye, P. J.;
DiMichele, L.; Dormer, P.; Reider, P. J. A practical synthesis of
a COX-2 specific inhibitor. J. Org. Chem. 2000, 65, 8415-8420.
(16) Rordorf, C.; Kellett, N.; Mair, S.; Ford, M.; Milosavljev, S.;
Branson, J.; Scott, G. Gastroduodenal tolerability of lumiracoxib
vs. placebo and naproxen: a pilot endoscopic study in healthy
male subjects. Aliment. Pharmacol Ther. 2003, 18, 533-541.
(17) Berenbaum, F.; Grifka, J.; Brown, J. P.; Zacher, J.; Moore, A.;
Krammer, G.; Dutta, D.; Sloan, V. S. Efficacy of lumiracoxib in
osteoarthritis: a review of nine studies. J. Int. Med. Res. 2005,
33, 21-41.
(18) Khanapure, S. P.; Garvey, D. S.; Young, D. V.; Ezawa, M.; Earl,
R. A.; Gaston, R. D.; Fang, X.; Murty, M.; Martino, A.; Shumway,
M.; Trocha, M.; Marek, P.; Tam, S. W.; Janero, D. R.; Letts, L.
G. Synthesis and structure-activity relationship of novel, highly
potent metharyl and methcycloalkyl cyclooxygenase-2 (COX-2)
selective inhibitors. J. Med. Chem. 2003, 46, 5484-5504.
(19) Julemont, F.; Leval, X.; Michaux, C.; Renard, J.-F.; Winum, J.-
Y.; Montero, J.-L.; Damas, J.; Dogne, J.-M.; Pirotte, B. Design,
synthesis, and pharmacological evaluation of pyridinic analogues
of nimesulide as cyclooxygenase-2 selective inhibitors. J. Med.
Chem. 2004, 47, 6749-6759.
(9) Prasit, P.; Wang, Z.; Brideau, C.; Chan, C. C.; Charleson, S.;
Cromilish, W.; Ethier, D.; Evans, J. F.; Ford-Hutchinson, A. W.;
Gauthier, J. Y.; Gordon, R.; Guay, J.; Gresser, M.; Kargman, S.;
Kennedy, B.; Leblanc, Y.; Leger, S.; Mancini, J.; O’Neill, G. P.;
Ouellet, M.; Percival, M. D.; Perrier, H.; Riendeau, D.; Rodger,
I.; Tagari, P.; Therien, M.; Vickers, P.; Wong, E.; Xu, L.-J.;
Young, R. N.; Zamboni, R.; Boyce, S.; Rupniak, N.; Forrest, M.;
Visco, D.; Patrick, D. The discovery of rofecoxib, {MK 966, Vioxx,
4-(4′-methylsulfonylphenyl)3-phenyl-2(5H)-furanone], an orally
active cyclooxygenase-2 inhibitor. Bioorg. Med. Chem. Lett. 1999,
9, 1773-1778.
(10) Talley, J. A.; Brown, D. L.; Carter, J. S.; Masferrer, M. J.;
Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel,
B. S.; Seibert, K. 4-[5-Methyl-3-phenylisoxazol-4-yl]-benzene-
sulfonamide, valdecoxib: A potent and selective inhibitor of
COX-2. J. Med. Chem. 2000, 43, 775-777.
(11) Scheen, A. J. Withdrawal of rofecoxib (Vioxx): what about
cardiovascular safety of COX-2 selective non-steroidal anti-
inflammatory drugs? Rev. Med. Liege 2004, 59, 565-569.
(12) Furberg, C. D.; Psaty, B. M.; FitzGerald, G. A. Parecoxib,
valdecoxib, and cardiovascular risk. Circulation 2005, 111, 249.
(13) Kimmel, S. E.; Berlin, J. A.; Reilly, M.; Jaskowiak, J.; Kishel,
L.; Chittams, J.; Strom, B. L. Patients exposed to rofecoxib and
celecoxib have different odds of nonfatal myocardial infarction.
Ann. Intern. Med. 2005, 142, 157-164.
(14) Riendeau, D.; Percival, M. D.; Brideau, C.; Charleson, S.; Dube,
D.; Ethier, D.; Falgueyret, J.-P.; Friesen, R. W.; Gordon, R.;
Greig, G.; Guay, J.; Manacini, J.; Ouellet, M.; Wong, E.; Xu, L.;
Boyce, S.; Visco, D.; Girad, Y.; Prasit, P.; Zamboni, R.; Rodger,
I. W.; Gresser, M.; Ford-Hutchinson, A. W.; Young, R. N.; Chan,
C.-C. Etoricoxib (MK-0663): Preclinical profile and comparison
(20) Khanapure, S. P.; Augustyniak, M. E.; Earl, R. A.; Garvey, D.
S.; Gordon, L. G.; Martino, A. M.; Murty, M. G.; Schwalb, D. J.;
Shumway, M. J.; Trocha, A. M.; Young, D. V.; Zemtseva, I. S.;
Janero, D. R. A potent and highly selective cyclooxygenase-2
(COX-2) inhibitor from a novel, pyridyl metharyl series. Pre-
sented at the 228th National Meeting of the American Chemical
Sociey, Philadelphia, PA, August 22-26, 2004; Paper MEDI 243.
(21) Parker, K. A.; Kallmerten, J. Approaches to anthracyclines. 2.
Regiospecific annulative quinone synthesis. J. Org. Chem. 1980,
45, 2620-2625.
(22) Khanapure, S. P.; Garvey, D. S. Use of highly reactive, versatile
and air-stable palladium-phosphinous acid complex [(t-Bu)2P-
(OH)]2PdCl2 (POPd) as a catalyst for the optimized Suzuki-
Miyaura cross-coupling of less reactive heteroaryl chlorides and
arylboronic acids. Tetrahedron Lett. 2004, 45, 5283-5286.
(23) Liu, H.; Huang, X.; Shen, J.; Luo, X.; Li, M.; Xiong, B.; Chen,
G.; Shen, J.; Yang, Y.; Jiang, H.; Chen, K. Inhibitory mode of
1,5-diarylpyrazole derivatives against cyclooxygenase-2 and
cyclooxygenase-1: molecular docking and 3D QSAR analyses.
J. Med. Chem. 2002, 45, 4816-4827.
(24) Soliva, R.; Almansa, C.; Kalko, S. G.; Luque, F. J.; Orozco, M.
Theoretical studies on the inhibition mechanism of cyclooxyge-
nase-2. Is there a unique recognition site. J. Med. Chem. 2003,
46, 1372-1382.
(25) Young, J. M.; Panah, S.; Satchawatcharaphong, C.; Cheung, P.
S. Human whole blood assays for inhibition of prostaglandin G/H
synthase-1 and -2 using A23187 and lipopolysaccharide stimula-
tion of thromboxane B2 production. Inflammation Res. 1996, 45,
246-253.
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