1,5-Diarylpyrrole-3-acetic acids and esters as novel classes of potent and highly selective cyclooxygenase-2 inhibitors

Article abstract of DOI:10.1021/jm049121q

A small set of substituted 1,5-diarylpyrrole-3-acetic and -glyoxylic acid derivatives have been synthesized, and their cyclooxygenase (COX-1 and COX-2) inhibiting properties have been evaluated. Some compounds proved to be highly selective COX-2 inhibitors, and their affinity data have been rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-2 binding site.

Full text of DOI:10.1021/jm049121q

3428
J. Med. Chem. 2005, 48, 3428-3432
Brief Articles
1,5-Diarylpyrrole-3-acetic Acids and Esters as Novel Classes of Potent and
Highly Selective Cyclooxygenase-2 Inhibitors
Mariangela Biava,*,† Giulio Cesare Porretta,† Andrea Cappelli,‡ Salvatore Vomero,‡ Fabrizio Manetti,‡
Maurizio Botta,‡ Lidia Sautebin,§ Antonietta Rossi,§ Francesco Makovec,# and Maurizio Anzini*,‡
Dipartimento di Studi di Chimica e Tecnolgia delle Sostanze Biologicamente Attive, Universita` “La Sapienza”, P.le A. Moro 5,
I-00185 Roma, Italy, Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and
Development, Universita` di Siena, Via A. Moro, 53100 Siena, Italy, Dipartimento di Farmacologia Sperimentale, Universita` di
Napoli “Federico II”, Via D. Montesano 49, I-80131 Napoli, Italy, and Rotta Research Laboratorium S.p.A., Via Valosa di
Sopra 7, 20052 Monza, Italy
Received November 3, 2004
A small set of substituted 1,5-diarylpyrrole-3-acetic and -glyoxylic acid derivatives have been
synthesized, and their cyclooxygenase (COX-1 and COX-2) inhibiting properties have been
evaluated. Some compounds proved to be highly selective COX-2 inhibitors, and their affinity
data have been rationalized through docking simulations in terms of interactions with a
crystallographic model of the COX-2 binding site.
Introduction
moieties were reminiscent of indometacin (11) and of
the above “coxib” family, respectively (Chart 1).
Nonsteroidal antiinflammatory drugs (NSAIDs) rep-
resent the standard therapy for the management of in-
flammation and pain. However, because NSAIDs indis-
criminately inhibit both isoforms of cyclooxygenase
(COX) (constitutive COX-1, responsible for cytoprotec-
tive effects; inducible COX-2, responsible for inflamma-
tory effects), they are associated with well-known side
effects at the gastrointestinal level (mucosal damage,
bleeding) and less frequently at the renal level.1 On the
other hand, it is known that selective inhibitors of
COX-2 can provide antiinflammatory agents devoid of
the undesirable effects associated with classical, non-
selective NSAIDs.2 As a consequence, the search for
specific inhibitors of COX-2 by means of modifications
of well-known nonselective agents has been largely pur-
sued and increasing interest has been devoted to the
synthesis of the diaryl heterocyclic class.3 In fact, DUP-
697 (1, Chart 1) and NS398 (2) were the first COX-2
selective compounds identified4 and the structure of 1
was the starting point for the synthesis of selective
inhibitors, which include recently marketed celecoxib5
(SC58635, Celebrex, 3), rofecoxib6 (MK-966, Vioxx, 4),
valdecoxib7 (5) (and its water-soluble prodrug pare-
coxib,8 6), and etoricoxib9 (7). As part of our research
program, aimed at discovering new pyrrole-containing
antiinflammatory agents, we focused our attention on
the synthesis of 1,5-diarylpyrrole-3-acetic acids and
esters (8-10) as new COX-2 selective inhibitors in
which the pyrroleacetic and vicinal diaryl heterocyclic
Discussion
The synthesis of the target compounds is shown in
Scheme 1. Briefly, the reaction of 4-(methylthio)benzal-
dehyde with methyl vinyl ketone10 was shown to be very
versatile and high-yielding in the preparation of the 1,4-
diketone 12, which was transformed into the corre-
sponding 4-methylsulfonyl derivative 13 by means of
Oxone oxidation.11 Compound 13, heated in the presence
of the appropriate amine according to the usual Paal-
Knoor (thermal) condensation, cyclized to yield the
expected 3-unsubstituted 1,5-diarylpyrrole 14 in satis-
factory yield after prolonged reflux. The construction of
the acetic acid chain was achieved by regioselective
acylation12 of 14 with ethoxalyl chloride in the presence
of pyridine to give derivatives 8. The R-keto esters (8)
were reduced by means of triethylsilane13 in trifluoro-
acetic acid to give pyrroleacetic esters (9), which in turn
were hydrolyzed with a solution of potassium hydroxide
in methanol/THF/H2O to afford the expected acids (10)
in good yields.
Biological evaluation of the title compounds showed
that the insertion of the acetic moiety in the coxib-like
scaffold gives rise to very potent and selective COX-2
inhibitors, the activities of which are presented in Table
1. Among them, three compounds (namely, 9a, 9c, and
10c) showed very interesting biological activity profiles,
their affinity toward COX-2 being comparable to that
of 3 (0.04, 0.06, and 0.11 µM versus 0.079 µM, respec-
tively) and COX-1/COX-2 selectivity ranging from >900
to >2500, even better than 4 (>800).
* To whom correspondence should be addressed. For M.B.: phone,
+39 (0)6 4991 3812; fax, +39 (0)6 4991 3133; e-mail, mariangela.biava@
uniroma1.it. For M.A.: phone, +39 (0)577 234173; fax, +39 (0)577
234333; e-mail, anzini@unisi.it.
To rationalize the results obtained, the new pyrrole
derivatives were submitted to a two-step computational
protocol consisting of molecular docking calculations and
structural optimization of the complexes obtained, with
the aim of investigating the possible interaction modes
† Universita` “La Sapienza”.
‡ Universita` di Siena.
§ Universita` di Napoli “Federico II”.
# Rotta Research Laboratorium S.p.A.
10.1021/jm049121q CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/12/2005

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3429
Chart 1
Scheme 1a
a Compounds: 8a, R ) H; 8b, R ) Me; 8c, R ) CF3; 9a, R ) H; 9b, R ) Me; 9c, R ) CF3; 10a, R ) H; 10b, R ) Me; 10c, R ) CF3.
Reagents and conditions: (i) CH2dCHCOCH3, NEt3, EtOH, 75-80 °C, 20 h, thiazolium; (ii) Oxone, MeOH/H2O, room temp, 2 h; (iii)
RPhNH2, TiCl4, toluene, room temp, 10 h; (iv) EtOCOCOCl, Pyr, CH2Cl2, 0 °C, 4 h; (v) Et3SiH, CF3COOH, room temp, 24 h; (vi) KOH,
EtOH, reflux, 2 h.
Table 1. In Vitro Inhibition of COX-1 and COX-2 by
Compounds 8-10
nary calculation was set to check if the program
Autodock15 could be considered as a reliable tool for
investigating the binding mode of the diaryl five-
membered compounds into the binding site of COX-2.
In particular, to set the optimal run parameters of
Autodock and to verify that they could be used to
successfully dock flexible diaryl five-membered inhibi-
tors within the COX-2 active site, the crystallographic
complex between COX-2 and SC-55816 (3a) was used as
a control structure. A total of 10 Autodock runs were
performed with different parameter sets (the optimal
run parameters are reported in the Supporting Infor-
mation). As a result, the first ranked cluster (among a
total number of 17 clusters) contained 43 conformations
in the same orientation within the binding site, with
respect to 3a, and the first conformation of the inhibitor
was characterized by a root-mean-square deviation of
0.27 Å (calculated on the heavy atoms) with respect to
the crystal structure, showing a very good agreement
between the experimental and the calculated coordi-
nates. Considering that the control docking trial was a
success, Autodock was thus used to find the best
orientations and conformations of the new inhibitors
COX-1 COX-2 % inhib
% inhib
IC50
IC50
of COX-2 of COX-2 COX-1/COX-2
compd
(µM)
(µM)
(10 µM)a
(1 µM)a
(SI)b
8a
8b
8c
9a
9b
9c
>100
>100
>100
>100
>100
>100
>100
>100
>100
5.1
4.3
54
77
43
>23
1.9
33
>92
9.9
51
33
>10
0.04
0.48
0.06
1.0
84
79
>2500
>208
>1600
>100
>200
>900
64.5
81
67
87
80
10a
100
100
100
96.4
100
100
43
10b
0.43
0.11
0.079
0.012
0.009
74
10c
69
celecoxibc
rofecoxibc
67
>10
84.1
67.9
>800
0.22
indometacinc 0.002
a Results are expressed as the mean of three experiments, of
the % inhibition of PGE2 production by test compounds with
respect to control samples. b In vitro COX-2 selectivity index
[IC50(COX-1)/IC50(COX-2)]. c See ref 20.
of such inhibitors within the COX-2 binding site.
Moreover, Grid maps14 were calculated for some probe
atoms or groups to evaluate the regions of best interac-
tion between inhibitors and macromolecule. A prelimi-

3430 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Brief Articles
group of Arg120 in a portion of the COX-2 binding site,
referred to as the “classical NSAID’s carboxylate binding
site”.16 The ethyl group pointed toward the solvent-
accessible surface and made hydrophobic contacts with
Val116 and Tyr355 possible. Finally, the methyl sub-
stituent at position 2 of the pyrrole ring was sandwiched
between the side chains of Val349 and Ala527 with
positive hydrophobic interactions. Details of computer
simulations on 9a and 9b have been reported in the
Supporting Information, as well as the results from Grid
calculations. Transformation of the ethyl ester side
chain into the corresponding acidic derivatives did not
significantly influence the activity of the methyl and
trifluoromethyl derivatives, in agreement with what was
previously reported, suggesting that position 3 of pyrrole
seemed much more permissive and tolerant to a number
of substituents and functional groups.11 In fact, 10c
showed an activity only twice lower than the corre-
sponding ester, while the activities of 10b and 9b were
comparable to each other. In contrast, 10a was found
to be 25 times less active than the corresponding ester
derivative 9a. Inspection of the alignment mode of 3a
and the new pyrrole derivatives within the COX-2
binding site suggested that the CF3 group, crucial for
the binding of 3 and 3a,17 could be replaced among
pyrrole derivatives by larger substituents (i.e., an acidic
function and the corresponding ethyl ester) without
affecting the activity, as shown by the affinity and
selectivity data of the new pyrrole compounds. More-
over, literature reports showed that pyrrole derivatives
bearing small substituents (such as Br and F) also
retained high affinity for COX-2 but with a large
decrease in selectivity because of the higher COX-1
affinity.11 Taken together, these findings suggested that
the role of CF3 in the binding of coxib derivatives was
carried out by the ester (or acidic) function and by the
methyl substituent at position 2 of the new pyrroles, as
shown by docking simulations and Grid maps.
Figure 1. Orientation of the optimized first ranked conforma-
tion (belonging to the first of 53 clusters) of 9c (displayed
following the atom type color codes) in comparison with the
cocrystallized inhibitor SC-558 (red, ball-and-stick) within the
COX-2 binding site. Three major regions of interactions
between 9c and the macromolecule can be discerned: (1) the
“hydrophobic pocket”16 (blue), (2) the “selectivity site” (orange),
and (3) the “classical NSAID’s carboxylate binding site”
(white). An accessory hydrophobic site (pink) can profitably
interact with the methyl group at position 2 of 9c. For the
sake of clarity, only a few amino acid residues of the COX-2
binding site are represented while the hydrogen bonds involv-
ing the ester side chain of 9c are omitted.
within the COX-2 binding site. The complexes obtained
from Autodock calculations and subsequent structural
optimization showed that the five-membered ring and
the diaryl systems of 9c and 3a are oriented in a similar
way (Figure 1). As previously reported,11 the vicinal
diaryl arrangement was responsible for the optimal
effectiveness in this series of compounds. In agreement
with this statement, computational simulations showed
that the two benzene rings were located within two of
the three most important binding pockets of the COX-2
binding site. In particular, the p-trifluorophenyl moiety
at position 1 of the pyrrole ring of 9c was found to be
superimposed on the p-bromophenyl group at position
1 of the co-crystallized inihibitor, occupying the “hydro-
phobic pocket” (following the notation used by Kurum-
bail and co-workers)16 delimited by the lipophilic and
aromatic side chains of Leu384, Tyr385, Trp387, and
Phe518. The side chain of the last residue formed the
wall separating the hydrophobic site from the “selectiv-
ity site” (see below). Moreover, the p-methylsulfonylphe-
nyl moiety of 9c corresponded to the p-sulfonamidophe-
nyl of 3a, filling a region of space called the selectivity
site.16 The oxygen atoms of the methylsulfone group of
9c interacted by means of hydrogen bonds with the
backbone NH group of Phe518 (2.14 Å) and with the
NH2 group of the Gln192 side chain (2.47 Å), while the
phenyl ring at position 5 was embedded in a hydropho-
bic region, making lipophilic contacts with the side
chains of both Leu352 and Val523 possible. Finally, the
ester chain of 9c, superimposed to the trifluoromethyl
group of 3a, was involved with its oxygen atoms in a
network of three hydrogen bonds with the guanidino
Conclusions
Two computational approaches were applied to the
new inhibitors, based on molecular docking/structural
optimization and on the generation of Grid maps for
different probes. Results from calculations led to the
identification of a binding mode for the pyrrole deriva-
tives, to the rationalization of their major structure-
activity relationships, and finally to the suggestion of
structural modifications of the compounds studied with
the aim of obtaining new derivatives with higher affinity
for COX-2. For this purpose, the synthesis and biological
evaluation of new compounds are now being carried out
and definitive results will be reported in due course.
Experimental Section
Chemistry. All chemicals used were of reagent grade.
Yields refer to purified products and are not optimized. Melting
points were determined in open capillaries on a Gallenkamp
apparatus and are uncorrected. Microanalyses were carried
out by means of a Perkin-Elmer 240C or a Perkin-Elmer series
II CHNS/O analyzer, model 2400. Merck silica gel 60 (230-
400 mesh) was used for column chromatography. Merck TLC
plates and silica gel 60 F254 were used for TLC. 1H NMR
spectra were recorded with a Bruker AC 200 spectrometer in
the indicated solvent (TMS as internal standard). The values
of the chemical shifts are expressed in ppm, and the coupling

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3431
constants (J) are expressed in Hz. Mass spectra were recorded
on a Varian Saturn 3 or a ThermoFinnigan LCQ-deca spec-
trometer.
mixture was made alkaline with 40% aqueous ammonia (10
mL) and extracted with CHCl3 (250 mL). The organic solution
was dried and evaporated in vacuo. The resulting residue was
chromatographed on silica gel, eluting with CHCl3 to give a
solid that after recrystallization from hexane/ethyl acetate
afforded the required product.
General Procedure for the Preparation of 1,5-Dia-
rylpyrrole-3-acetic Acids (10a-c). These compounds were
prepared from the appropriate pyrroleacetic ester by alkaline
hydrolysis in a solution of 2 M KOH. The synthetic procedure
is described below. To a solution of 2 M KOH (20 mL) in EtOH
(15 mL), the suitable 1,5-diarylpyrrole-3-acetic ester (1.5 mmol)
was added. The reaction mixture was refluxed for 2 h. The
solution was then cooled and acidified with 3 N HCl (10 mL)
and extracted with dichloroethane (20 mL). The organic
solution was dried and evaporated in vacuo. The resulting
residue was recrystallized with ethanol to afford the expected
acid in good yields.
1-[4-(Methylthio)phenyl]pentane-1,4-dione (12). To a
solution of 4-(methylthio)benzaldehyde (12 mL, 0.09 mol) in
ethanol (30 mL) were added triethylamine (19.5 mL, 0.14 mol),
methyl vinyl ketone (5.8 mL, 0.07 mol), and 3-ethyl-5-(2-
hydroxyethyl)-4-methylthiazolium bromide (3.53 g, 0.014 mol).
The mixture was heated at 75-80 °C for 20 h under nitrogen
and then cooled. The solvent was removed under reduced
pressure, and the residue was treated with 2 N HCl (300 mL).
After extraction with dichloromethane, the organic layer was
washed with aqueous sodium hydrogen carbonate and water.
The organic fractions were dried over Na2SO4, filtered, and
concentrated to give a crude orange liquid (16.2 g). After
chromatography on silica gel (hexane/ethyl acetate, 7/3 v/v),
the desired 12 was isolated (yield 70%) as a light-yellow solid
that after recrystallization from hexane gave an analytical
sample as light-yellow needles. The analytical data, melting
point, and 1H NMR spectrum were consistent with those
reported in the literature.11
1-[4-(Methylsulfonyl)phenyl]pentane-1,4-dione (13). To
a solution of 12 (7.8 g, 35 mmol) in methanol (150 mL), Oxone
(37.7 g, 61.4 mmol) dissolved in water (150 mL) was added
over 5 min. After the mixture was stirred at 25 °C for 2 h, the
reaction mixture was diluted with water (400 mL) and
extracted with CH2Cl2 (3 × 400 mL). The organic layer was
washed with brine (200 mL) and water (200 mL) and dried
(Na2SO4). After filtration and concentration, the crude material
was chromatographed (silica gel; hexane/ethyl acetate, 3/1) to
give 13 (yield 90%) as a yellowish solid that after recrystalli-
zation from hexane/ethyl acetate gave an analytical sample
as white needles. The analytical data, melting point, and NMR
spectrum were consistent with those reported in the litera-
ture.11
General Procedure for the Preparation of 1,5-Dia-
rylpyrroles 14a-c. These compounds were prepared by
means of the Paal-Knorr reaction as shown in Scheme 1 by
condensing a 1,4-diketone with the appropriate amine. Briefly,
a mixture of diketone 13 (2.28 mmol) and the suitable amine
(2.5 mmol) in the presence of p-toluenesulfonic acid (30 mg)
in dry toluene (50 mL) was refluxed for 20 h using a Dean-
Stark apparatus. The reaction mixture was cooled, filtered,
and concentrated. The crude material was purified by flash
chromatography with a hexane/ethyl acetate (7/3 v/v) mixture
as the eluent to give the expected 1,5-diarylpyrrole as a solid
in satisfactory yield. Recrystallization from hexane/ethyl
acetate gave the required product.
General Procedure for the Preparation of Ethyl 1,5-
Diarylpyrrole-3-ylglyoxylic Esters (8a-c). These com-
pounds were prepared by reaction of ethoxalyl chloride with
the appropriate pyrrole in the presence of pyridine, as previ-
ously reported.12 A solution of pyridine (11 mmol) in CH2Cl2
was added to a strirred solution of ethoxalyl chloride (1.22 mL,
10 mmol) in CH2Cl2 (15 mL) at a rate that allowed the
temperature to be kept between -20 and -25 °C. Immediately
after, a solution of the pyrrole derivative (10 mmol) in CH2Cl2
(15 mL) at the same temperature was added. The solution was
stirred for 4 h at 0 °C, then washed sequentially with dilute
HCl and saturated aqueous NaCl solution. The organic solu-
tion was dried and evaporated in vacuo. Purification of the
residue by flash chromatography with ethyl acetate as eluent
gave a solid that after recrystallization from hexane/ethyl
acetate afforded the expected product.
Biology. Arachidonic acid was obtained from SPIBIO,
Paris, France. [3H-PGE2] was from Perkin-Elmer Life Sciences
(Milan, Italy). All other reagents and compounds used were
obtained from Sigma-Aldrich, Milan, Italy.
Cell Culture. The murine monocyte/macrophage J774 cell
line was grown in Dulbecco’s modified Eagle’s medium (DMEM)
supplemented with 2 mM glutamine, 25 mM Hepes, penicillin
(100 u/mL), streptomycin (100 µg/mL), 10% foetal bovine
serum (FBS), and 1.2% Na pyruvate (Bio Whittaker, Europe).
Cells were plated in 24-well culture plates at a density of 2.5
× 105 cells/mL or in 10 cm diameter culture dishes (1 × 107
cells/10 mL per dish) and allowed to adhere at 37 °C in 5%
CO2/95% O2 for 2 h. Immediately before the experiments, the
culture medium was replaced by a fresh medium without FBS
in order to avoid interference with radioimmunoassay,18 and
cells were stimulated as described.
COX-1 Activity. Cells were pretreated with the reference
standard or the test compounds (0.01-10 µM) for 15 min and
incubated at 37 °C for 30 min with 15 µM arachidonic acid in
order to activate the constitutive COX.18 Stock solutions of the
reference standard or test compounds were prepared in
dimethyl sulfoxide, and an equivalent amount of dimethyl
sulfoxide was included in control samples. At the end of the
incubation the supernatants were collected for the measure-
ment of PGE2 by radioimmunoassay.
COX-2 Activity. Cells were stimulated for 24 h with E. coli
lipopolysaccharide (LPS, 10 µg/mL) to induce COX-2 in the
absence or presence of the test compounds at the concentra-
tions previously reported. The supernatants were collected for
the measurement of PGE2 by radioimmunoassay.
Statistical Analysis. Triplicate wells were used for the
various conditions of the treatment throughout the experi-
ments. Results are expressed as the mean, of three experi-
ments, of the % inhibition of PGE2 production by test com-
pounds with respect to control samples. Data fit was obtained
using the sigmoidal dose-response equation (variable slope)
(GraphPad software). The IC50 values were calculated by the
GraphPad Instat program (GraphPad software).
Computational Details. All calculations and graphical
manipulations were performed on Silicon Graphics computers
(Origin 300 server and Octane workstations) using the soft-
ware package Autodock 3.0.5,15 Grid 21,14 and MacroModel
8.519 (equipped with the AMBER94 and OPLS-AA force field).
The program Autodock was used to evaluate the binding mode
of the new inhibitors and to explore their binding conforma-
tions within the COX-2 structure. Because Autodock does not
perform any structural optimization and energy minimization
of the complexes found, a molecular mechanics/energy mini-
mization (MM/EM) approach was applied to refine the Au-
todock output. Program Grid was used to map the COX-2
binding site onto a three-dimensional grid and to calculate for
each grid point the interaction energy (including contributions
from the van der Waals, electrostatic, and hydrogen bond
interactions) between a probe and all the protein atoms.
General Procedure for the Preparation of Ethyl 1,5-
Diarylpyrrole-3-acetic Esters (9a-c). These compounds
were prepared by reduction of the appropriate glyoxylic
derivative by means of triethylsilane in trifluoroacetic acid
(TFA)13 under nitrogen atmosphere at 0 °C. The procedure for
the synthesis of 9a-c is as follows. To a solution of the suitable
R-keto ester (2.3 mmol) in trifluoroacetic acid (TFA) (9 mL)
stirred at 0 °C under nitrogen, triethylsilane (0.75 mL, 4.7
mmol) was slowly added, and the mixture was stirred for 30
min at room temperature. At the end of the reaction, the
Acknowledgment. We thank Dr. R. Soliva for
kindly providing us with the inhibitor parameters to

3432 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Brief Articles
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implement the Amber force field, Laura Salvini
(C.I.A.D.S., University of Siena, Italy) for the recording
of mass spectra, and Prof. Stefania D’Agata D’Ottavi
for the careful reading of the manuscript. Thanks are
due to the Italian MIUR for financial support.
Supporting Information Available: Experimental de-
tails (chemistry, pharmacology, and molecular modeling) and
results from elemental analysis. This material is available free
of charge via the Internet at http://pubs.acs.org.
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