Rational design of 6-methylsulfonylindoles as selective cyclooxygenase-2 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2004.06.075

The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation of a conformationally more rigid 3-aroyloxy substituent onto the 6-methylsulfonylindole scaffold led to selective, but considerably less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the indole 2-substituent of 3-arylthio-6-methylsulfonylindole inhibitors led to modulation of the COX-2 human whole blood (HWB) potency and selectivity. The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation of a conformationally more rigid 3-aroyloxy substituent onto the 6- methylsulfonylindole scaffold led to selective, but considerably less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the indole 2-substituent of 3-arylthio-6-methylsulfonylindole inhibitors led to modulation of the COX-2 human whole blood (HWB) potency and selectivity.

Full text of DOI:10.1016/j.bmcl.2004.06.075

Bioorganic & Medicinal Chemistry Letters 14 (2004) 4741–4745
Rational design of 6-methylsulfonylindoles as selective
cyclooxygenase-2 inhibitors
Jeffrey A. Campbell,* Viola Bordunov, Chris A. Broka, Michelle F. Browner,
James M. Kress, Tara Mirzadegan, Chakk Ramesha, Bong F. Sanpablo, Russell Stabler,
Patricia Takahara, Armando Villasenor, Keith A. M. Walker,
Jin-Hai Wang, Mary Welch and Paul Weller
Roche Palo Alto, 3431 Hillview Ave, Palo Alto, CA 94304, USA
Received 22 April 2004; revised 21 June 2004; accepted 23 June 2004
Available online 20 July 2004
Abstract—The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using
rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation
of a conformationally more rigid 3-aroyloxy substituent onto the 6-methylsulfonylindole scaffold led to selective, but considerably
less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the indole 2-substituent of 3-arylthio-6-methylsulfonylin-
dole inhibitors led to modulation of the COX-2 human whole blood (HWB) potency and selectivity.
Ó 2004 Elsevier Ltd. All rights reserved.
SO2NH2
SO2CH3
Selective inhibitors of cyclooxygenase-2 (COX-2) have
been successful in the clinic as effective anti-inflamma-
tory drugs having fewer side effects than traditional non-
steroidal anti-inflammatory drugs, (NSAIDs).1 Typical
side effects exhibited by NSAIDs include ulcers and
bleeding in the GI tract and are attributed to inhibition
of the cyclooxygenase-1 isozyme (COX-1), which plays a
role in gastric cytoprotection. Thus, selective inhibitors
of COX-2 over COX-1 are effective anti-inflammatory
drugs without having an adverse ulcerogenic side effect
profile.2 Celecoxib (1)3 and rofecoxib (2)4 were the first
effective selective COX-2 inhibitors to reach the market,
followed by second generation drugs valdecoxib (3)5 and
etoricoxib (4)6 shown in Figure 1. All of these drugs
have very similar structures, locked in almost identical
conformations. Using molecular overlays of these
known drugs and our own naphthalene based inhibi-
tors7 in the COX-2 active site,8 it was hypothesized that
the introduction of 3-aroyl, 3-arylmethyl, 3-aryloxy and
3-arylthio moieties into a 6-methylsulfonyl-2-methylin-
dole framework would lead to potent and selective
COX-2 inhibitors (Fig. 2).9
N
N
O
CF3
O
celecoxib (1)
rofecoxib (2)
SO2CH3
SO2NH2
Cl
O
N
N
N
etoricoxib (4)
valdecoxib (3)
Figure 1. Marketed selective COX-2 inhibitors.
A series of 3-aryloxy-6-methanesulfonyl-2-methylin-
doles (8) were then prepared as shown in Scheme 1 using
a Fisher indole synthesis as the key step.9 The requisite
precursor hydrazine 6 was prepared in 60–70% overall
yield from m-thioanisidine 5 using Oxonee, followed
by HNO2/SnCl2 reduction. Aryloxyacetone analogues
of 7 were either purchased commercially or were pre-
pared in 75–95% yield from the chloroacetone alkyla-
tion of the corresponding phenol using K2CO3 and KI
in refluxing acetone. Hydrazine 6 was condensed with
the requisite substituted aryloxyacetone analogue 7 in
Keywords: Selective COX-2 inhibitor; Indole; COX-2; X-ray structure.
*
Corresponding author at present address: PTC Therapeutics, 100
Corporate Court, South Plainfield, NJ 07080, USA. Tel.: +1-908-
2227000x122; fax: +1-908-2227231; e-mail: jcampbell@ptcbio.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.06.075

4742
J.A.Campbell et al./ Bioorg.Med.Chem.Lett.14 (2004) 4741–4745
O
Ar
a,b,c
NH2 MeS
d,e
N
N
H
MeO2S
MeS
H
10
5
12
f,e,g
Ar
Ar
X
h,e
i
N
H
N
N
H
MeO2S
MeO2S
MeO2S
H
13 X=S
15 X=S(O)
16 X=SO2
14
11
Scheme 2. Reagents and conditions: (a) pyruvaldehyde dimethylacetal,
I2 (cat), benzene, D; (b) NaBH4, MeOH; (c) BF3 (gas), CH2Cl2; (d)
Ar(C@O)NMe2, POCl3 neat, 20min D; 60min D, 10; (e) Oxonee, 50%
MeOH/H2O; (f) BOC2O, 4-DMAP, CH3CN; (g) TFA, CH2Cl2; (h)
ArSH, PIFA, (CF3)2CHOH; (i) Ar(C@O)H, TMSOTF, CH2Cl2,
Et3SiH.
Figure 2. Molecular overlay of 2-aryloxyindole 8a (shown in purple)
with selective COX-2 inhibitors celecoxib (1), rofecoxib (2) and
valdecoxib (3).
a,b
O
O
+
ArO
S
O
NHNH2
MeS
NH2
to these strongly acidic conditions. Thus, the indole NH
of 10 was first protected as the N-BOC derivative.
Sulfide oxidation using Oxonee and TFA mediated
cleavage of the intermediate N-BOC 2-methyl-6-methyl-
sulfonyl-indole gave 11 in 60% overall yield from 10.9,11
The direct 3-aroylation of indole 11 proved to be unsuc-
cessful using either Friedel–Crafts or Vilsmeyer–Hack
acylation conditions.12 An alternative aroylation–oxida-
tion sequence using Vilsmayer–Hack conditions on 6-
methylthioindole 10 with a subsequent Oxonee oxida-
tion of the intermediate 3-aroyl-6-methylthioindole,
proved successful affording the 3-aroyl analogues 12 in
50–80% overall yield. It is believed that direct oxidation
of the 3-aroyl-6-methylthioindole is possible due to sta-
bilization of the indole by the 3-aroyl moiety.
6
7
5
c,d
Ar
O
S
O
Ar
O
O
+
O
N
H
N
S
O
H
9
8 (Major or exclusive product)
Scheme 1. Reagents and conditions: (a) Oxonee, 50% MeOH/H2O;
(b) NaNO2, 6M HCl, SnCl2; (c) PhH, reflux 2h; (d) PCl3 (1equiv),
CH2Cl2, rt.
refluxing benzene, followed by concentration and treat-
ment with stoichiometric PCl3 in CH2Cl2 to afford either
the desired Fisher indole product 8 pure or 8/9 as a 2:1
mixture.10 The 6-methylsulfonyl isomer 8 was isolated as
the sole product in an average 30% yield for the majority
of the analogues.
Although direct aroylation of 11 was not possible, the
direct 3-thioarylation or 3-arylmethylation of indole 11
was made feasible through the development of novel
synthetic methodology. Synthetic details regarding these
methods have been reported elsewhere.13 Thus, the 3-
arylthio analogues (13) were in general prepared directly
from 6-methylsulfonyl indole 11 and the corresponding
arylthiols using bis(trifluoroacetoxy)iodo benzene
(PIFA) in (CF3)2CHOH in approximately 62–76%
yield.13a The 3-arylmethyl analogues (14) were also pre-
pared directly from 12 and the corresponding benzalde-
hydes in 67–88% yield using TMSOTf and Et3SiH in
CH2Cl2.13b Sulfoxide and sulfone analogues, 15 and
16, respectively, were prepared from the Oxonee oxida-
tion of aryl sulfide 13.14
Due to the uncertain regiochemical control exhibited in
the Fisher indole reaction leading to the 3-aryloxy ana-
logues, this approach was not explored for the syntheses
of the 3-aroyl, 3-arylthio and 3-arylmethyl derivatives of
6-methylsulfonyl-2-methylindole (12, 13 and 14, respec-
tively). It was envisioned that a route involving direct 3-
aroylation, 3-arylthiolation or 3-arylmethylation of 2-
methyl-6-methylsulfonylindole 11 would be the most
optimal in terms of the efficiency for analogue genera-
tion (Scheme 2).9,11 Indole 10 was synthesized using a
three step sequence in 60% overall yield, starting with
condensation of 5 with pyruvaldehyde dimethylacetal,
reduction of the intermediate imine using NaBH4/
MeOH, followed by a gaseous BF3-mediated indole ring
closure.9,11 Attempts at direct sulfide oxidation of the 6-
SMe moiety of indole 10 using Oxonee failed presuma-
bly due to instability of the electron rich indole nucleus
In order to prepare analogues of 3-arylthio indole 13,
where the 2-methyl moiety was replaced with more
hydrophilic substituents, the preparation of 2-carboxy-
methyl-6-methylsulfonylindole 19 served as the starting
point (Scheme 3).9,15 The synthesis began with the con-
densation of methylazidoacetate using NaOMe in the
presence of benzaldehyde 17 at ꢀ20 to 0°C for 2days

J.A.Campbell et al./ Bioorg.Med.Chem.Lett.14 (2004) 4741–4745
4743
Table 1. Cyclooxygenase activity of various 3-substituted 2-methyl-6-
methylsulfonylindole analogues16
O
c
a,b
H
CO2Me
XAr
N
H
MeS
MeS
18
17
19
CH3
N
MeO2
S
H
SAr
Compd XAr
IC50 COX-2
(lM)
IC50 COX-1
(lM)
d
CO2Me
CO2Me
N
N
H
MeO2S
MeO2S
H
Enzyme HWB Enzyme HWB
20
e,f,g,h
8a
8b
OPh(4-F)
OPh(2,4-DiF)
OPh(4-Cl)
0.030
0.11
2.0
4.1
3.8
1.6
4.1
1.72
2.6
2.2
0.77
4.8
5.2
11.3
8.4
5.6
5.1
5.5
ND
ND
>40
39.5
30.0
>30
25.8
100
>40
>40
ND
9.0
37
33
i,j or i,k,l
SAr
8c
0.300
0.200
0.11
12
SAr
8/9d
8e
OPh(4-OMe)
OPh(2,4-DiCl)
(C@O)Ph(4-F)
6
33
Y
Y
N
N
H
12a
12d
13a
13b
13d
13f
14a
14b
14c
14d
14g
15a
16a
0.664
2.44
3.50
55.7
18.2
18
MeO2S
MeO2S
H
(C@O)Ph(4-OMe) 1.09
SPh(4-F)
0.020
ND
21 Y=CO2H
25 Y=CH2OH
SPh(2,4-DiF)
SPh(4-OMe)
S(2-Pyridyl)
CH2Ph(4-F)
CH2Ph(2,4-DiF)
CH2Ph(4-Cl)
CH2Ph(4-OMe)
CH2Ph(2-Cl)
S(@O)Ph(4-F)
SO2Ph(4-F)
22 Y=CONH2
26 Y=CH2OCO2Me
27 Y=CH2SO2Me
23 Y=CONR'R''
24 Y=CN
0.47
1.78
0.080
0.26
0.26
0.27
0.07
>40
>40
ND
>40
>40
>40
>45
>40
ND
ND
30
63.9
98
Scheme 3. Reagents and conditions: (a) methyl azidoacetate, NaOMe,
ꢀ20 to 0°C (2days); (b) toluene, 110°C for 3h; (c) Oxonee, 2:1:1
MeOH/THF/H2O; (d) ArSH, PIFA, (CF3)2CHOH; (e) LiOH, 1:1
THF/H2O; (f) ClCOCOCl, DMF (cat), CH2Cl2; (g) 0.5M NH3 in
dioxane or R0R00NH/THF; (h) (CF3CO)2O, pyridine; (i) 1.5M DIBAL/
toluene, THF; (j) Ac2O, Et3N, THF; (k) MsCl, Et3N, CH2Cl2; (l)
NaSO2Me, DMF.
71.1
7.3
118
ND
ND
followed by thermolysis of the intermediate vinylogous
azido ester in refluxing toluene for 3h to afford indole
methyl sulfide 18 in 60–70% overall yield. Oxonee oxi-
dation of indole 18 then gave the desired precursor 2-
carboxymethyl-6-methylsulfonylindole 19 in 85–90%
yield without requiring protection of the indole NH
moiety. Incorporation of the 3-thioaryl moiety was
accomplished by treatment of 19 with the corresponding
arylthiols using PIFA in (CF3)2CHOH to afford 20 in an
impressive 74–88% yield.13a
stituted indoles, in general, displayed excellent potency
and selectivity (>100) for inhibition of COX-2 with 4-
fluoro and 2,4-diflurorophenyl substitution (8a–b, 13a–
b, 14a–b). Other aryl substitution patterns gave inferior
results, though a certain tolerance was noted for 2-
chloro and 4-chlorophenyl substituted analogues (8c,
8e, 14c and 14g). The 3-aroyl analogues, although selec-
tive against purified enzyme, were considerably less po-
tent. Similarly, in the HWB assay, the 3-aroyl analogues
were COX-2 selective, but not very potent (ꢁ1lM). This
is consistent with the notion that for significant binding
of the inhibitor to the COX-2 active site, the linker di-
rectly bound to indole 3-position must have significant
conformational flexibility (see Fig. 2). Smaller flexible
tethers such as 3-aryloxy (8), 3-arylthio (13) and 3-aryl-
methyl (14) led to much more potent inhibitors than lar-
ger conformationally constrained tethers such as the 3-
aroyl (12), 3-sulfinyl (15) and 3-sulfonyl linkers (16). A
representative 3-aryloxy compound (8a) showed excel-
lent in vitro COX-2 enzyme potency (0.030lM) and
selectivity over COX-1 (>1300). This is consistent with
the molecular overlay of the known marketed selective
COX-2 inhibitors shown in Figure 2 and the crystal
structure of 8a shown in green obtained in the active site
of COX-2 (Fig. 3). In this crystal structure, the 4-fluoro-
phenyl ring of 8a occupies a top hydrophobic pocket
(Phe-529, Phe-381, Tyr-385, Trp-387), the indole N–H
The carbomethoxy moiety of this indole could be con-
verted to a variety of hydrophilic 2-substituents at the
acid oxidation state. Hydrolysis of 20 using LiOH in
50% THF/H2O gave acid 21 in >97% yield. This acid
was then reacted with oxalyl chloride to form the acid
chloride and subsequently treated with the correspond-
ing primary, secondary or tertiary amines to afford
amides 22 and 23 in approximately 70–80% overall yield
from 20. Nitrile 24 was prepared in 85% yield via dehy-
dration of primary amide 22 using (CF3CO)2O in pyr-
idine. Alternatively, the 2-carbomethoxy indole ester
20 could be reduced to alcohol 25 using DIBAL and
then converted to hydrophilic 2-substituents at a lower
oxidation state. Indole 25 was acylated to methyl car-
bonate 26 using methyl chloroformate, converted to an
intermediate mesylate and alkylated with NaSO2Me in
DMF to afford the corresponding methylsulfone ana-
logue 27.
˚
makes a 2.8A H-bond with the oxygen of the Tyr-355
hydroxyl group, and the side pocket Arg-513 makes a
˚
3.0A H-bond with the oxygen of the 6-MeSO2 moiety.
Consistent with this structural data is that replacement
of the indole NH with a N–Me moiety led to a 10–20-
fold reduction of in vitro enzyme COX-2 potency of
All the indoles were tested for inhibition against COX-2
and COX-1 using an in vitro radiometric assay and hu-
man whole blood (HWB) assay. Details of these assays
have been described elsewhere.9 As shown in Table 1,
the 3-aryloxy, 3-arylthio and 3-arylmethyl-2-methyl sub-

4744
J.A.Campbell et al./ Bioorg.Med.Chem.Lett.14 (2004) 4741–4745
Table 2. Cyclooxygenase activity of 2-substituted-6-methylsulfonyl-3-
thioaryloxyindole analogues16
SAr
Y
N
H
MeO2S
Compd Ar moiety
Y
COX-2
COX-2 COX-1
Enzyme
(IC50, lM)
HWB
(IC50, lM)
20a
21a
22a
24a
20b
22b
23b
24b
24g
24h
Ph(4-F)
Ph(4-F)
Ph(4-F)
Ph(4-F)
CO2Me
CO2H
CONH2
CN
0.80
>40
1.21
1.01
0.38
2.24
>40
0.94
0.13
0.33
1.1
9.3
ND
>40
2.30
0.38
>40
ND
1.27
0.57
1.09
ND
>40
>125
17.2
>40
ND
>60
>67
8.1
Ph(2,4-DiF) CO2Me
Ph(2,4-DiF) CONH2
Ph(2,4-DiF) CONHMe
Ph(2,4-DiF) CN
Ph(2-Cl)
Ph(2-Cl),
4-OMe
CN
CN
Figure 3. X-ray/FlexX docked structure of 8a in COX-2 active site.
25a
26g
27g
Ph(4-F)
Ph(2-Cl)
Ph(2-Cl)
CH2OH
CH2OAc
0.42
>40
5.90
ND
ND
>100
ND
ND
the respective inhibitor (data not included in tables). It is
noteworthy that the observed X-ray structure (shown in
green) matched very closely to the docked structure
(shown in blue) predicted from FlexX active site model-
ling (Fig. 3).17a–c The only notable difference was that
the 3-aryloxy moiety of 8a was rotated out of plane in
the crystal structure relative to that obtained in the
FlexX docked structure.17d
CH2SO2Me >40
for the 3-arylthio analogues (Table 2) could modulate
the COX-2 HWB potency and selectivity (compounds
20b, 24a, 24b, 24g and 25a). The in vitro COX-2 enzyme
potency was affected also, as inhibitors with small sub-
stituents such as the 2-cyano were best tolerated (24a,
24g and 24h) and inhibitors having large substituents
such as secondary amides (23b), acetoxymethyl (26g)
and methylsulfonylmethyl (27g) were devoid of signifi-
cant biological activity.
The main difference in the binding pocket of COX-1 and
COX-2 as depicted in Figure 4, is the larger access to the
side pocket in COX-2.8 The access to the side pocket is
hindered by presence of Ile-523 in COX-1 instead of a
smaller residue (Val-523) in COX-2. There is also an-
other key difference in this pocket, the presence of
Arg-513 in COX-2 versus a His-513 in COX-1. This
Arginine has been previously shown to make a key H-
bond interaction with most selective COX-2
inhibitors.8,18
In vivo testing is reported on a select number of indole
analogues (Table 3). In the rat, excellent oral plasma lev-
els (35–316lM AUC) at 10mg/kg correlated with excel-
lent inhibition (54–92%) of carrageenan induced
inflammation (rat air pouch model) at 1mg/kg. Details
of the rat carrageenan air pouch model have been de-
scribed elsewhere.9 Compounds 8a, 14b and 24b also
showed good rat plasma half-lives (6.2, 4.1 and 6.3h,
respectively), with respectable corresponding Cmax
plasma levels (2.9, 6.7 and 23.2lM, respectively).
Against a panel of liver P450 isozymes, the IC50s of
compound 8a were >15lM with the exception of 2C19
(7lM), while the IC50s of compound 14b were >16lM
against all the isozymes, except 2C9 (4.4lM).
The COX-2 HWB potency and selectivity for 8a and
other related 3-substituted-2-methylindole analogues,
however, were at least one order of magnitude lower
than for the in vitro COX-2 enzyme results. It was sub-
sequently discovered that variation of the 2-substituent
In conclusion, the introduction of 3-arylmethyl, 3-aryl-
oxy and 3-arylthio moieties into a 6-methylsulfonylin-
dole framework using rational drug design led to
potent, selective COX-2 inhibitors having efficacy in a
rat carrageenan air pouch model. Incorporation of a
conformationally more rigid 3-aroyloxy substituent
onto the 6-methylsulfonylindole scaffold led to selec-
tive, but considerably less potent COX-2 inhibitors.
Variation of the hydrophilicity and size of the indole
Figure 4. Origin of COX-2 selectivity of indole 8a.
2-substituent of a 3-arylthio-6-methylsulfonylindole

J.A.Campbell et al./ Bioorg.Med.Chem.Lett.14 (2004) 4741–4745
4745
Table 3. In vivo activity of select indole analogues
Visco, D.; Patrick, D. Bioorg.Med.Chem.Lett. 1999, 9,
1773.
5. Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.;
Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rodgers,
R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert,
K. J.Med.Chem. 2000, 43, 775.
XAr
Y
N
MeO2S
H
6. Friesen, R. W.; Brideau, C.; Chan, C. C.; Charleson, S.;
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.
7. Rotstein, D. M.; Sjogren, E. B. Ger.Offen. 1998, p 32 (DE
19803003 A1 19980730).
8. Luong, C.; Miller, A.; Barnett, J.; Chow, J.; Ramesh, C.;
Browner, M. F. Nat.Struct.Biol. 1996, 3, 927.
9. Broka, C. A.; Campbell, J. A. PCTInt. Appl. WO
0329212, 2003, p 46.
Compd XAr moiety
Y
Rat AUC
Admin. PO
(lM, mg/kg)
T1/2 Rat
(h)
Airpouch
(% inh,
mg/kg)
8a
8b
OPh(4-F)
Me 35, 10
Me ND
Me ND
6.2
54, 1.0
OPh(2,4-DiF)
SPh(4-F)
SPh(2,4-DiF)
ND 52, 1.0
ND 78, 1.0
ND 76, 1.0
13a
13b
14b
14g
24b
24g
Me 118, 10
CH2Ph(2,4-DiF) Me 72, 10
4.1
ND 62, 1.0
6.3 92, 1.0
ND 85, 1.0
85, 1.0
CH2Ph(2-Cl)
SPh(2,4-DiF)
SPh(2-Cl)
Me ND
CN 316, 10
CN 56, 10
10. Baccolini, G.; Dalpozzo, R.; Todesco, P. E. J.Chem.Soc.,
Perkin Trans.1 1988, 971.
11. Allais, A.; Rosseau, G.; Peterfalvi, N. Eur.J.Med.Chem-
Chim.Ther. 1975, 10, 187.
12. Ketcha, D. M.; Gribble, G. W. J.Org.Chem. 1985, 50,
5451.
inhibitor led to modulation of the COX-2 HWB potency
and selectivity.
13. (a) Campbell, J. A.; Broka, C. A.; Gong, L.; Walker, K. A.
M.; Wang, J.-H. Tetrahedron Lett. 2004, 45, 4073, and
references cited therein; (b) Campbell, J. A.; Broka, C. A.;
Dankwardt, J.; Bordunov, V.; Kress, J.; Wang, J. H.;
Walker, K. A. M.; Wang, J. H. Tetrahedron Lett. 2004, 45,
3793, and references cited therein.
14. Caddick, S.; Aboutayab, K.; West, R. I. J.Chem.Soc,.
Chem.Commun. 1995, 1354.
15. (a) Adams, R. E.; Press, J. P.; Deegan, E. G. Synth.
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1373.
Acknowledgements
We would like to acknowledge the contributions of Paul
Cheung, Su-Chen Hsieh, Wen Chen Hsu, William Tao,
Steve Terao and Amy Zhou in our department of drug
metabolism and pharmacokinetics. We would also like
to thank Dr. Leyi Gong for proof reading of this
manuscript.
16. The IC50 data provided within these tables are a combi-
nation of single point and averaged value taken from
multiple measurements.
References and notes
17. FlexX is a flexible-docking algorithm based on an incre-
mental construction strategy, incorporated as a Sybyl
module. For a pertainent FlexX review article and FlexX
docking procedural references, see: (a) Kramer, B.; Metz,
G.; Rarey, M.; Lengauer, T. Med.Chem.Res. 1999, 9(7/8),
463; (b) Kramer, B.; Rarey, M.; Lengauer, T. Proteins
Struct.Funct.Genet. 1999, 37, 228; (c) Rarey, M.; Kramer,
B.; Lengauer, T.; Klebe, G. J.Mol.Biol. 1996, 261, 470;
(d) The X-ray coordinates of 8a bound to COX-2 are
currently deposited at Roche Palo Alto.
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