Thiazole analogues of the NSAID indomethacin as selective COX-2 inhibitors

Article abstract of DOI:10.1016/S0960-894X(01)00212-8

The carboxyl group of the NSAID indomethacin was replaced with a variety of substituted thiazoles to obtain a series of potent, selective inhibitors of COX-2. Additional substitutions were made at the 1-position and 5-position of the indole of indomethacin.

Full text of DOI:10.1016/S0960-894X(01)00212-8

Bioorganic & Medicinal Chemistry Letters 11 (2001) 1325–1328
Thiazole Analogues of the NSAID Indomethacin as Selective
COX-2 Inhibitors
Keith W. Woods,* Richard W. McCroskey, Michael R. Michaelides, Carol K. Wada,
Keren I. Hulkower and Randy L. Bell
Abbott Laboratories, 100 Abbott Park Rd., D-47S AP10/307, Abbott Park, IL 60064-6101, USA
Received 12 February 2001; accepted 19 March 2001
Abstract—The carboxyl group of the NSAID indomethacin was replaced with a variety of substituted thiazoles to obtain a series of
potent, selective inhibitors of COX-2. Additional substitutions were made at the 1-position and 5-position of the indole of indo-
methacin. # 2001 Elsevier Science Ltd. All rights reserved.
Nonsteroidal antiinflammatory drugs (NSAIDs) are
commonly used for the treatment of ailments such as
pain, fever, and inflammation. Classical NSAIDs are
nonselective inhibitors of both known isozymes of cyclo-
oxygenase (COX-1 and COX-2). COX-1 is expressed
constitutively in most cell types and plays a role in gas-
tric cytoprotection and in maintaining normal renal
function. The COX-2 pathway involves an induction
mechanism resulting in elevated expression in inflamed
tissues. These differences provide the rationale for the
development of selective COX-2 inhibitors.1 Two COX-
2 inhibitors, celecoxib2 and rofecoxib,3 have been
approved and are currently being marketed.
indomethacin to be selective COX-2 inhibitors.7 Pre-
viously, Merck reported that extending the acetic acid
chain as well as replacing the N-benzoyl results in COX-
2 selectivity.8 We wish to report that replacement of the
indomethacin carboxyl group with a variety of sub-
stituted thiazoles leads to a series of potent and selective
inhibitors of COX-2.
A series of 4-substituted thiazoles was prepared as
shown in Scheme 1. The indomethacin carboxyl group
was activated with isobutylchloroformate then treated
with ammonia gas to give the amide. The amide was
allowed to react with phosphorus pentasulfide to form
the thioamide. Reaction of the thioamide with a variety
of a-bromoketones gave the 4-substituted thiazoles (3).
The typical side effects seen with the use of NSAIDs
include ulcers and bleeding and incidence of renal pro-
blems with chronic therapy, presumably resulting from
the inhibition of the COX-1 isozyme. Selective inhibi-
tion of COX-2 appears to provide an advantage for
inflammation and pain relief without the negative side
effects observed with traditional NSAIDs.4
Indomethacin (1) is a nonselective inhibitor of both
COX-1 and COX-2.5 A high throughput screening assay
using recombinanat enzyme, however, showed the gly-
cerol ester of indomethacin to be approximately 400
times selective for COX-2 (IC50 for COX-1=12.4 mM;
IC50 for COX-2=30 nM).6 Marnett and co-workers
have recently reported ester and amide derivatives of
*Corresponding author. Fax: +1-847-938-5034; e-mail: keith.
woods@abbott.com
Scheme 1. Reagents and reaction conditions: (a) isobutyl-
chloroformate; (b) NH3 (g); (c) P4S10, THF/dioxane; (d) THF, rt, 24 h.
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00212-8

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K. W. Woods et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1325–1328
Treatment of indomethacin with thionyl chloride fol-
lowed by trimethylsilyldiazomethane and HBr yielded
Table 1. Cyclooxygenase activity of thiazole analogues of indo-
methacin with substitutions in the 4-position of the thiazole6
the corresponding a-bromoketone 4 (Scheme 2).
Subsequent reaction with selected thioamides gave the
2-substituted thiazole analogues (5).
Replacement of the p-chlorobenzoyl group of indo-
methacin with p-bromobenzyl is reported to generate a
COX-2 selective inhibitor.8 Corresponding thiazole
analogues with additional changes in the 5-position of
indole (8) are prepared as shown in Scheme 3. Fischer
indole synthesis is carried out between the appropriately
substituted phenyl hydrazine and ethyl levulinate.
Treatment with sodium hydride and 4-bromobenzyl
bromide followed by ester hydrolysis gives the car-
boxylic acid which can be further elaborated as de-
scribed in Scheme 1 or 2. The structures of all compounds
were established by proton NMR and mass spectrometry.
Compd
R
COX-2
IC50 (nM)
COX-1
(% inhibition
@ 10 mM)
3a
12
28
3b
3c
3d
14
0.3
12
16
27
17
A variety of thiazole analogues of indomethacin have
been prepared and were tested for their inhibitions of
human recombinant prostaglandin endoperoxidase H
synthase-1 and -2 (PGHS-1 and PGHS-2, also referred
to as COX-1 and COX-2, respectively).6 These com-
pounds were shown to be highly selective, potent inhib-
itors of COX-2. Little activity against COX-1 (<57%
inhibition at 10 mM) was observed.
3e
3f
21% @ 100 nM
33% @ 100 nM
13
15
3g
3h
3i
120
35
23
18
35
12
36% @ 100 nM
8
3j
85% @ 100 nM
75% @ 100 nM
Scheme 2. Reagents and reaction conditions: (a) SOCl2, CH2Cl2; (b)
trimethylsilyldiazomethane, THF; (c) HBr, Et2O; (d) THF, rt, 24 h.
3k
3m
3n
3p
CO2Et
COOH
iPr
40% @ 100 nM
2% @ 100 nM
1% @ 100 nM
1
6
36
3q
3r
3s
1
20
11
13
7
6% @ 100 nM
Scheme 3. Reagents and reaction conditions: (a) NaOAc, HOAc, tol-
uene; (b) NaH, 4-bromobenzyl bromide, DMF; (c) NaOH.

K. W. Woods et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1325–1328
1327
Table 2. Cyclooxygenase activity of thiazole analogues of indo-
methacin with substitutions in the 2-position of the thiazole6
Aromatic substitutions in the 4-position of the thiazole
(Table 1) were more active than the corresponding
2-substituted derivatives (Table 2).
Removal of the aromatic ring and substituting directly
onto the thiazole ring resulted in decreased activity. The
amine (5a), amide (5b), carboxylic acid (3n), ethyl ester
(3m), and alkyl (3p) derivatives all showed minimal
COX-2 activities.
Compd
R
COX-2
IC50 (nM)
COX-1
(% inhibition
@ 10 mM)
Replacement of the p-chlorobenzoyl group of indo-
methacin with p-bromobenzyl is reported to generate a
COX-2 selective inhibitor.8 Replacing the p-chloro-
benzoyl with p-bromobenzyl in the thiazole derivatives,
however, resulted in decreased activity (Table 3). Com-
parison of the 4-(p-bromophenyl) analogues (3c and 9a)
shows the N-(p-chlorobenzoyl) compound to be 100
times more potent than the N-(p-bromobenzyl) deriva-
tive.
5a
5b
NH2
390
15.5 mM
27
4% @ 100 nM
5c
5d
5e
5f
45% @ 100 nM
0
47
57
18
24
20
The 5-methoxy substitution on the indole appears to be
important for activity as well (Table 3). The 5-bromo
(9e, 9f, and 9g) and 5-fluoro (9h, 9i, and 9j) substitutions
both resulted in significant losses of potencies.
75% @ 100 nM
16% @ 100 nM
42% @ 100 nM
We have demonstrated that potent and selective inhibi-
tors of human recombinant COX-2 can be prepared by
replacing the indomethacin carboxyl group with a vari-
ety of substituted thiazoles. Aromatic substitutions in
the 4-position of the thiazole are preferred.
5g
Table 3. Cyclooxygenase activity of N-(p-bromophenyl)indole thia-
zole analogues with substitutions in the 5-position of the indole6
References and Notes
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9a
9b
9c
9d
9e
9f
9g
9h
9i
OMe
OMe
OMe
OMe
Br
Br
Br
FBr
FCl
FNO
Br
Cl
COOH
NO2
Br
30
7
3
2
40
9
13
4
1
10% @ 100 nM
7
7% @ 100 nM
9% @ 100 nM
7% @ 100 nM
Cl
NO2
25% @ 100 nM
37% @ 100 nM
40% @ 100 nM
0
7
9j
1
2
The thiazole analogues with aromatic moieties were in
general extremely potent inhibitors of COX-2. Halogen
substitution on the phenyl ring resulted in good potency
against COX-2 (ꢀ14 nM), with the p-bromophenyl
analogue showing subnanomolar activity (ex. 3c). The
benzothiophene and naphthalene derivatives had single
digit nanomolar activity (e.g., 3q and 3r, respectively).
6. Human recombinant COX-1 and COX-2 were cloned and
expressed in baculovirus (Sf9). Sf9 microsomes were pre-incu-
bated with inhibitor for 60 min prior to the addition of ara-
chidonic acid (10 mM). PGE2 produced was analyzed by
enzyme linked immunoassay.

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K. W. Woods et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1325–1328
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