Substituted pyrrol-1-ylacetic acids that combine aldose reductase enzyme inhibitory activity and ability to prevent the nonenzymatic irreversible modification of proteins from monosaccharides

Article abstract of DOI:10.1021/jm0209477

Starting from the known inhibitory activity of (3-benzoylpyrrol-1-yl)acetic acid (I) and (2-benzoylpyrrol-1-yl)acetic acid (II), a series of 3-aroyl and 2,4-bis-aroyl derivatives (54-75) were synthesized and tested for inhibition of aldose reductase, an e

Full text of DOI:10.1021/jm0209477

J . Med. Chem. 2003, 46, 417-426
417
Su bstitu ted P yr r ol-1-yla cetic Acid s Th a t Com bin e Ald ose Red u cta se En zym e
In h ibitor y Activity a n d Ability To P r even t th e Non en zym a tic Ir r ever sible
Mod ifica tion of P r otein s fr om Mon osa cch a r id es
Ioannis Nicolaou and Vassilis J . Demopoulos*
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki,
Thessaloniki 54124, Greece
Received May 28, 2002
Starting from the known inhibitory activity of (3-benzoylpyrrol-1-yl)acetic acid (I) and
(2-benzoylpyrrol-1-yl)acetic acid (II), a series of 3-aroyl and 2,4-bis-aroyl derivatives (54-75)
were synthesized and tested for inhibition of aldose reductase, an enzyme involved in the
appearance of diabetic complications. It was found that a number of the tested compounds
exhibited considerable activity in the micromolar range. Important structural features for the
potent compounds is the presence of substituents with relatively low Hammett σ values and/
or moieties which increase their overall aromatic area. The most active derivative was the
[2,4-bis(4-methoxybenzoyl)pyrrol-1-yl]acetic acid (75), with potency favorably compared to
known ARIs such as tolrestat, epalrestat, zopolrestat, and fidarestat. Four selected derivatives
were also evaluated for their ability to interfere with the oxidative modification of serum
albumin in an in vitro experimental glycation model of diabetes mellitus. All of them showed
considerable activity, comparable to the known inhibitor trolox. Our results, taken together,
indicate that compound 75 combines favorably two biological activities directly connected to a
number of pathological conditions related to the chronic diabetes mellitus.
In tr od u ction
(e.g., through hyperosmosis or depletion of NADPH,
myo-inositol, and taurine).11 In diabetic patients, fruc-
tose is also formed intracellularly from sorbitol by the
action of sorbitol dehydrogenase (SDH, EC 1.1.1.14) and
can reach the same concentrations of glucose in certain
tissues.12 Glucose and, especially, fructose can react
with proteins to form alpha keto-amines via Amadori
rearrangements. This can lead, through Maillard type
reactions, to advanced glycation end products (AGE) and
damage of proteins.13 Glucose and fructose can undergo
transition metal catalyzed oxidations, which contribute
to acceleration of modifications in the tissues that are
involved in late onset diabetic complications.13a,b,14
Oxidative stress also induces the activity with changes
in expression of the AR enzyme and transforms it to a
state that is less sensitive to several of its inhibitors.15
Furthermore, AGE induce increases in aldose reductase
mRNA and protein.16 Finally, oxidative stress and the
resulting lipid peroxidation is implicated in the alterna-
tion of glucose transport in Type II diabetes.17
Diabetes mellitus is a universal health problem, and
Type 2 diabetes is a disease fast approaching epidemic
proportions throughout the world.1 The clinical profile
of diabetic subjects is often worsened by the presence
of several serious long-term complications,2 which mainly
account for the economic burden in the treatment of the
patients.3 The Diabetes Control and Complications
Trial,4 as well as related trials,5 demonstrated that the
more severe and sustained the degree of hyperglycemia,
the more likely it is that the chronic complications of
diabetes will develop. Ideally, lowering glycated hemo-
globin6 by intensive glucose control will help to prevent
the devastating complications of neuropathy, retinopa-
thy, nephropathy, and vascular disease. For many
people with diabetes, however, the achievement and
maintenance of euglycemia is extremely difficult,7 while
a correlation between hyperinsulinemia and coronary
artery disease is recognized.8 Consequently, researchers
have turned to pharmaceutical intervention as a way
to prevent complications in a background of hypergly-
cemia.7,9
Hyperglycemia causes ‘hyperglysolia’,10 within cells
of vulnerable tissues. Although the molecular basis for
the pathogenic effects of hyperglysolia remains to be
proven, substantial evidence point to certain biochemi-
cal processes. Glucose can be reduced to sorbitol by
aldose reductase (AR, EC 1.1.1.21), the first enzyme of
the polyol pathway. Sorbitol’s concentration is, thus,
marked increased in some cells possessing insulin
independent glucose transport. The increased accumu-
lation of sorbitol has been linked to cellular damage
Although a considerable number of compounds have
been synthesized and shown to be effective AR inhibi-
tors (ARIs),18 the only ARI available as a drug is Ono
Pharmaceutical’s epalrestat in J apan.19 However, as the
inhibition of the polyol pathway is considered to be a
promising approach to control diabetes complications,10,20
the already marketed epalrestat as well as new chemical
entities are investigated in clinical trials for their
efficacy.21
Various antioxidants,22,23 as well as compounds not
necessarily acting by an antioxidant mechanism,24,25
have been found to inhibit AGE formation. In clinical
trials,26,27 a number of them exerted beneficial effects
to diabetic patients.
* To whom correspondence should be addressed. Tel.: +30(31)-
0997626 or +30(31)0997659. Fax: +30(31)0997622. E-mail: vdem@
pharm.auth.gr.
Based on the above, in the present study we synthe-
sized the compounds 54-75 shown in Figures 1 and
10.1021/jm0209477 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/21/2002

418 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3
Nicolaou and Demopoulos
F igu r e 1. Synthesized target compounds 54-75 based on the structures of I and II.
tested them in vitro for their ability to inhibit AR.
Furthermore, for selected more active ones we evaluated
their ability to interfere with the oxidative modification
of serum albumin in an in vitro experimental glycation
model of diabetes mellitus.22b
The compounds 54-72 in Figure 1 are derivatives of
(3-benzoylpyrrol-1-yl)acetic acid (I), which has been
previously shown28 that is an ARI. The changes, which
were made in the structure of I, were generally selected
as to confer variability to the physicochemical properties
of the target compounds. The biphenyl, naphthyl, and
benzofuran rings have also been identified to belong to
the class of privileged substructures for protein bind-
ing.29 In compounds 64-66 the additional pyrrole ring
was introduced in the premise to increase their overall
reductive ability.30
The compounds 73-75 (Figure 1) combine structural
features of I and of (2-benzoylpyrrol-1-yl)acetic acid (II).
The latter is also, although comparatively weaker, an
ARI.28 In compounds 73-75 there is a gradual addition
of methoxy groups, aiming to an increase of the parts
of the molecules, which could stabilize free radicals,
based on the captodative principle.31
Ch em istr y. For the synthesis of the target pyrrole-
1-ylacetic acid derivatives 54-75, we followed the
general methodology outlined in Scheme 1. Previously,
it has been reported the synthesis of the starting aryl-
(1H-pyrrol-3-yl)methanones 1-11 (Figure 2)32a as well
as of the 2-phenyl-1-(1H-pyrrol-3-yl)ethanone (12)32b and
of the (1H-indol-3-yl)phenylmethanone (13).32c Also, (3-
chlorophenyl)(1H-pyrrol-3-yl)methanone (14) was syn-

Pyrrol-1-ylacetic Acid Aldose Reductase Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3 419
F igu r e 2. Structures of the previously reported32a starting pyrrolylmethanones 1-11.
Sch em e 1. General Methodology Followed for the Synthesis of the Target Compounds 54-75
Sch em e 2. Synthesis of the Pyrrolylmethanone 19
thesized in a similar way as the reported preparation
of its p-chloro isomer 4.32a
hydrochloride36) or 1,4-dichloro-1,4-dimethoxybutane
and Amberlyst A-21.37 The best results were obtained
under acidic conditions with 4-cloropyridinium hydro-
chloride as the catalyst. The formed intermediates 17
and 18 were used in the next steps without further
purification; the final ketone 19 was isolated after
hydrolysis of the benzenesulfonyl group of 18.
The sequence of reactions followed for the preparation
of (1H-pyrrol-3-yl)(4-pyrrol-1-ylphenyl)methanone 19 is
shown in Scheme 2. This involved the introduction32a
of a nitrobenzoyl substituent in position-3 of 1-benzene-
sulfonyl-1H-pyrrole (15), reduction of the nitro group
under hydrogen transfer hydrogenation conditions,33
and formation of a pyrrole ring with Clauson-Kaas type
methodologies. The experimental conditions studied for
the Clauson-Kaas type reactions utilized either 1,4-
dimethoxytetrahydrofurane and an acid catalyst (acetic
acid,34 phosphorus pentoxide,35 and 4-cloropyridinium
The sequence of reactions followed for the preparation
of (1,2-dihydrobenzofuran-5-yl)(1H-pyrrol-3-yl)metha-
none 23 and (benzofuran-5-yl)(1H-pyrrol-3-yl)metha-
none 25 is shown in Scheme 3. The methodology was
an adaptation of a previously reported preparation of a
number of benzofuran derivatives which, however, did

420 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3
Nicolaou and Demopoulos
Sch em e 3. Synthesis of the Pyrrolylmethanones 23, 25, 28-30
Sch em e 4. Synthesis of Pyrrolylacetic Acids 54-56, 58-70, and 72-75
not contain a pyrrole ring.38a It involved a Friedel-
Crafts condensation of 1-benzenesulfonyl-1H-pyrrole-3-
carbonyl chloride (20)38b with 2,3-dihydrobenzofuran
(21) at a low temperature, followed by either hydrolysis
to 23 or oxidation and then hydrolysis to 25. Attempts
to oxidize 23 to 25 resulted in a substantial bromination
of the pyrrole ring.
The synthesis of (5-aroyl-1H-pyrrol-3-yl)arylmetha-
nones (28-30, Scheme 3), from which 29 is a new one,
was attained under Friedel-Crafts acylation conditions
of aryl(1H-pyrrol-3-yl)methanones 26 and 27.39
The general method for the formation of the aroyl
heterocyclic ethyl N-acetate derivatives 31-49 involved
nucleophilic substitution under the previously re-
ported28 phase transfer catalysis conditions (Scheme 4),
while the reduction of ethyl (3-benzoylpyrrol-1-yl)acetic
acid ethyl ester 5128 for the preparation of 52 was
performed under mild reductive conditions40 with the
combination of sodium cyanoborohydride and zinc iodide
(Scheme 4).
The formation of the final carboxylic acids 54-56,
58-70, and 72-75 was attained under basic hydrolytic
conditions, with best results obtained in an equimolar
mixture of 5% sodium hydroxide and dioxane (Scheme
4). The synthesis of (3-benzoylindol-1-yl)acetic acid (71)
from 13, via the intermediate (3-benzoylindol-1-yl)acetic
acid ethyl ester (50), has been previously described.41
The formation of the phenolic carboxylic acid 57 in-
volved the effect of boron tribromide42 on 33 followed
by basic hydrolysis of the resulting mixture that con-
tained the phenolic carboxylic ester and acid derivatives
53 and 57 (Scheme 5). Attempts to O-demethylate 33
with chlorothrimethylsilane/sodium iodide43 was unsuc-
cessful resulting in the isolation of only starting mate-
rial.
Resu lts a n d Discu ssion
The synthesized target compounds 54-75 were tested
in vitro for their ability to inhibit rat lens AR. It has
been shown that there is an approximately 85% se-

Pyrrol-1-ylacetic Acid Aldose Reductase Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3 421
Sch em e 5. Synthesis of Pyrrolylacetic Acid 57
Ta ble 1. Aldose Reductase Inhibitory Activity
% inhibition (SEM)a at concn
10-7 10-8
inhibitor
10-6
46 (2.5)
M
M
M
10-9
M
54
55
41 (4.3)
72 (6.5)
45 (3.5)
41 (3.5)
47 (6.0)
18 (5.6)
76 (0.5)
58 (2.5)
79 (5.5)
67 (4.3)
80 (1.0)
38 (4.5)
40 (4.0)
42 (4.0)
29 (3.8)
9 (6.5)
56
26 (1.0)
57
58
59
60
61
37 (3.0)
59 (3.2)
72 (1.0)
39 (2.0)
39 (1.5)
62
49 (4.5)
22 (2.0)
20 (5.9)
63
64
65
66
67
68
69
70
71
38 (3.8)
44 (3.0)
82 (1.5)
93 (7.0)
96 (0.5)
27 (2.0)
72
73
62 (2.0)
51 (6.0)
94 (2.5)
27 (1.5)
13 (5.5)
59 (3.9)
74
75
41 (4.2) IC50 ) 2.36 (0.64)b nM
Ic
IId
trolox
sorbinil
36 (2.0) at 10-5
12 (0.0) at 10-5
M
M
48% (0.5) at 2.5 × 10-7 Me
n ) 3. Mean (standard error from three determinations). c (3-Benzoylpyrrol-1-yl)acetic acid. (2-Benzoylpyrrol-1-yl)acetic acid.
a
b
d
e Reported28 IC50: 0.25 µM.
quence similarity between rat lens and human AR,
while the proposed active sites of both enzymes are
identical.45 The performed assay was based on the
spectrophotometric monitoring of NADPH oxidation,
which is proven to be a quite reliable method.46
possible steric hindrance during compound/enzyme
interaction (i.e. 66 vs 62, 68 vs 56 and 71 vs I) or the
reduced aromatic character of the benzofuran ring49 (i.e.
67 vs 63). Compounds 69 and 70 exhibited weak
inhibitory potency. Inspection of low energy conforma-
tions50 of these compounds reveals that their two
aromatic rings are almost perpendicular to each other,
while in the cases of the active methanone derivatives
these rings are almost in the same plane. This difference
could be an explanation of their low activity in the
particular in vitro experiment.
Compounds 64, 65, 74, and 75 were also tested for
their ability to inhibit in vitro the irreversible modifica-
tion of the model protein albumin (the most abundant
in the serum) in the presence of fructose (fructation) as
the glycating monosaccharide. Fructose, instead of
glucose (glucation), was chosen in the assay because is
known to be a more potent glycation agent.23 This
derives from the fact that its acyclic (open chain) form,
which is the reactive species, is approximately 10 times
that of glucose. Fructose is also elevated in those tissues
where the polyol pathway is active.12 The selection of
It was found (Table 1) that a number of the tested
compounds (56, 61-65, and 73-75) exhibited consider-
able activity in the micro molar range. The most active
derivative was compound 75, with potency favorably
compared to known ARIs. This is supported from the
indicative literature IC50 values, cited in parentheses,
for some well studied active inhibitors such as tolrestat
(35 × 10-9 M47a), epalrestat (10 × 10-9 M47b), zopolrestat
(3.1 × 10-9 M47c), and fidarestat (35 × 10-9 M47d).
Important structural features in the above-mentioned
potent compounds is the presence of substituents with
relatively low Hammett σ values and/or moieties which
increase their overall aromatic area. These mentioned
characteristics are not determinant for the biological
profile of the compounds 57, 66-68, and 71. An expla-
nation could be phenomena like the decrease of lipo-
philicity (i.e. 56: ClogP ) 1.936 vs 57: ClogP ) 1.619),48

422 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3
Nicolaou and Demopoulos
Ta ble 2. Glycation-Induced Fluorescence Changes of BSA and
Formation of DNPH-Reactive Carbonyl Groups in BSA Exposed
to Fructose. Effect of Inhibitors
gradually added an aqueous solution of NaH2PO2‚H2O (30%).
Addition of the phosphinate solution was continued until no
starting material remained. The mixture was filtered and the
filtrate poured into water (20 mL) and extracted with CH2-
Cl2. The combined extracts were dried (Na2SO4), and the
solvents were evaporated under reduced pressure to give crude
(1-benzenesulfonyl-1H-pyrrol-3-yl)(4-aminophenyl)metha-
none (17) (1.5 g) which was used directly in the next step.
relative
fluorescence
%
carbonyl groups
%
compd C (mM)
(R.U.)a
inhibn (nmol/mg BSA) inhibn
none
64
64
64
65
65
65
74
74
74
75
75
75
-
27.8 ( 2.5 (13)
16.4 ( 0.9 (4)b
21.0 ( 0.6(3)b
21.0 ( 1.1 (3)b
4.7 ( 0.4 (6)b
9.8 ( 0.2 (4)b
17.4 ( 0.7 (4)b
6.9 ( 0.3 (6)b
11.5 ( 0.9 (5)b
23.1 ( 1.1 (3)c
3.3 ( 0.4 (3)b
11.8 ( 0.9 (6)b
17.3 ( 0.5 (3)b
12.8 ( 0.5 (5)b
-
41
24
24
83
65
37
75
41
17
89
57
38
54
5.03 ( 0.6 (14)
not detectable
not detectable
1.55 ( 0.4b
not detectable
not detectable
not detectable
not detectable
1.7 ( 0.3 (6)b
4.38 ( 0.6 (5)c
not detectable
not detectable
2.52 ( 0.8 (4)b
3.44 ( 0.9 (5)b
-
100
100
69
100
100
100
100
66
5
2.5
1
5
2.5
1
5
2.5
1
5
2.5
1
A mixture of crude 17 (1.5 g), 4-chloropyridine hydrochloride
(0.97 g, 6.47 mmol), and 2,5-dimethoxytetrahydrofuran (0.88
g, 5.8 mmol) in dioxane (30 mL) was refluxed for 3 h under a
nitrogen atmosphere. The resulting solution was evaporated
under reduced pressure, and the residue was dissolved in Et2O,
dried over Na2SO4, and evaporated under reduced pressure.
The residue was dissolved in dioxane (50 mL), and to this a 5
N solution of NaOH (50 mL) was added. The reaction mixture
was vigorously stirred at room temperature for 24 h. The
organic layer was collected, and the aqueous was thoroughly
extracted with EtOAc (2 × 50 mL). The combined organic layer
and extracts were washed with saturated NaCl solution, dried
(Na2SO4), and evaporated under reduced pressure. The residue
was flash chromatographed with EtOAc/petroleum ether (3:
1) followed by recrystallization from toluene/petroleum ether
to provide the title compound (0.26 g, 24%): mp 172-173 °C;
IR (Nujol) 3200, 1610 cm-1; 1H NMR (CDCl3) δ 6.20-6.50 (m,
2H, pyrrolyl(phenyl)-3,4H), 6.60-6.90 (m, 2H, pyrrolyl-4,5H),
7.05-7.20 (m, 2H, pyrrolyl(phenyl)-2,5H), 7.25-7.60 (m, 3H,
pyrrolyl-2H and phenyl-3,5H), 7.90 (d, 2H, phenyl-2,6H, J )
8.3 Hz), 10.80 (br s, 1H, pyrrolyl-1H). Anal. (C15H12N2O) C,
H, N.
20
100
100
50
trolox
1
32
a
Results are means ( SD with number of samples in paren-
theses. P < 0.001. c P < 0.01 vs control according to Student’s t
test.
b
the compounds to be tested was based on a suitable
combination of three criteria: (a) AR inhibitory activity
in the micromolar range, (b) absence of putative mu-
tagenic moieties (e.g. biphenyl51), and (c) presence of
chemical characteristics which could contribute to an
increase of the antioxidant potential (e.g. an additional
pyrrole ring30 or substructures with captodative proper-
ties31).
It was found (Table 2) that the examined compounds
were moderately less effective in inhibiting the glyca-
tion-iduced fluorescence changes of bovine serum albu-
min (BSA) than the known22b proteins’ glycation inhibi-
tor trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-
carboxylic acid). However, they were generally more
effective than trolox to inhibit the formation of DNPH-
reactive carbonyl groups in BSA. Furthermore, it should
be mentioned that trolox is a weak AR inhibitor (Table
1).
The above results, taken together, indicate that [2,4-
bis(4-methoxybenzoyl)pyrrol-1-yl]acetic acid (75) com-
bines favorably two biological activities directly con-
nected to a number of pathological conditions related
to the chronic diabetes mellitus. Finally, a preliminary
(n ) 6) toxicity test showed that compound 75, at a dose
of 1 mmol (0.39 g)/kg ip did not produce any mortality
to experimental rats after a 24 h period.
(1-Ben zen esu lfon yl-1H-p yr r ol-3-yl)(2,3-d ih yd r oben zo-
fu r a n -5-yl)m eth a n on e (22). To a solution of 2,3-dihydroben-
zofuran (21) (0.52 g, 4.26 mmol) in CH2Cl2 (10 mL) at -10 °C
under a N2 atmosphere was added dropwise a solution of
1-benzenesulfonyl-1H-pyrrole-3-carbonyl chloride (20)38b (2 g,
7.42 mmol) in CH2Cl2 (10 mL) and then AlCl3 (0.6 g, 4.5 mmol).
After the addition was completed, the mixture was stirred for
an additional 1 h at -5 to -10 °C. The reaction was quenched
with ice and water and the product was extracted with CH2-
Cl2 (2 × 50 mL). The combined organic extracts were washed
with saturated NaCl solution, dried over Na2SO4, and evapo-
rated under reduced pressure. The residue was flash chro-
matographed with EtOAc/petroleum ether (5:1) followed by
recrystallization from toluene/petroleum ether to provide the
title compound (1.19 g, 79%): mp 168-170 °C; IR (Nujol) 1635
cm-1 1H NMR (CDCl3) δ 3.30 (t, 2H, dihydrobenzofuranyl-
;
3H, J ) 9.6 Hz), 4.65 (t, 2H, dihydrobenzofuranyl-2H, J ) 9.6
Hz), 6.65-6.85 (m, 2H, pyrrolyl-4,5H), 7.10-7.30 (m, 1H,
dihydrobenzofuranyl-7H), 7.45-8.00 (m, 8H, pyrrolyl-2H, di-
hydrobenzofuranyl-4,6H and C6H5SO2). Anal. (C19H15NO4S‚
0.1H2O) C, H, N.
(2,3-Dih yd r ob en zofu r a n -5-yl)(1H -p yr r ol-3-yl)m et h a -
n on e (23). Compound 22 (1 g, 2.83 mmol) was dissolved in
dioxane (50 mL), and to this a 5 N solution of NaOH (50 mL)
was added. The reaction mixture was vigorously stirred at
room temperature for 24 h. The organic layer was collected,
and the aqueous was thoroughly extracted with EtOAc (2 ×
100 mL). The combined organic layer and extracts were
washed with saturated NaCl solution, dried over Na2SO4, and
evaporated under reduced pressure. The residue was recrys-
tallized from toluene/petroleum ether to provide the title
compound (0.54 g, 90%): mp 111-112 °C; IR (Nujol) 3200,
1635 cm-1; 1H NMR (CDCl3) δ 3.20 (t, 2H, dihydrobenzofura-
nyl-3H, J ) 9.6 Hz), 4.60 (t, 2H, dihydrobenzofuranyl-2H, J
) 9.6 Hz), 6.60-6.80 (m, 2H, pyrrolyl-4,5H), 7.15-7.40 (m,
2H, pyrrolyl-2H and dihydrobenzofuranyl-7H), 7.60-7.85 (m,
2H, dihydrobenzofuranyl-4,6H), 9.50 (br s, 1H, pyrrolyl-1H).
Anal. (C13H11NO2) C, H, N.
Exp er im en ta l Section
Gen er a l Notes. Melting points are uncorrected and were
determined in open glass capillaries using a Mel-Temp II
apparatus. UV spectra were recorded either on a Perkin-Elmer
554 or on a Hitachi U-2001 spectrophotometer, IR spectra on
1
a Perkin-Elmer 597 spectrophotometer, and H NMR spectra
on a Bruker AW-80 spectrometer with internal TMS standard.
Elemental analyses were performed on a Perkin-Elmer 2400
CHN analyzer. Fluorescence was recorded on a Hitachi F-2000
spectrophotometer.
(3-Ch lor op h en yl)(1H-p yr r ol-3-yl)m eth a n on e (14). This
compound was synthesized in a similar way as the reported32a
preparation of its p-chloro-isomer 4 in a 76% yield: mp 104-
105 °C; IR (Nujol) 3200, 1610 cm-1; 1H NMR (CDCl3) δ 6.65-
6.80 (m, 2H, pyrrolyl-4,5H), 7.25-7.40 (m, 1H, pyrrolyl-2H),
7.40-7.85 (m, 4H, phenyl-H), 9.30 (br s, 1H, pyrrolyl-1H).
Anal. (C11H8NOCl) C, H, N.
Ben zofu r a n -5-yl-(1H-p yr r ol-3-yl)m eth a n on e (25). Com-
pound 22 (0.75 g, 2.12 mmol) was dissolved in CCl4 (75 mL),
and to the resulting solution was added N-bromosuccinimide
(0.368, 2.07 mmol) and a catalytic amount of dibenzoyl
peroxide. The mixture was refluxed under a N2 atmosphere
for 2 h, cooled to room temperature, filtered, and evaporated
(1H-P yr r ol-3-yl)(4-p yr r ol-1-ylp h en yl)m eth a n on e (19).
(1-Benzenesulfonyl-1H-pyrrol-3-yl)(4-nitrophenyl)methanone
(16)32a (1.63 g, 0.46 mmol) in tetrahydrofuran (20 mL) was
stirred with Pd-C (10%) (0.16 g), and to this suspension was

Pyrrol-1-ylacetic Acid Aldose Reductase Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3 423
under reduced pressure. The residue was dissolved in dioxane
(50 mL), and to this a 5 N solution of NaOH (50 mL) was
added. The reaction mixture was vigorously stirred at room
temperature for 24 h. The organic layer was collected, and the
aqueous was thoroughly extracted with EtOAc (2 × 100 mL).
The combined organic layer and extracts were washed with
saturated NaCl solution, dried over Na2SO4 and evaporated
under reduced pressure. The residue was flash chromato-
graphed with EtOAc/petroleum ether (4:1) followed by recrys-
tallization from toluene/petroleum ether to provide the title
compound (0.25 g, 57%): mp 140-141 °C; IR (Nujol) 3200,
1635 cm-1; 1H NMR (CDCl3) δ 6.65-6.95 (m, 3H, pyrrolyl-4,5H
and benzofuranyl-3H), 7.25-8.00 (m, 4H, pyrrolyl-2H and
benzofuranyl-4,6,7H), 8.05-8.25 (m, 1H, benzofuranyl-2H),
10.70 (br s, 1H, pyrrolyl-1H). Anal. (C13H9NO2) C, H, N.
[4-(4-Met h oxyb en zoyl)-1H -p yr r ol-2-yl]p h en ylm et h a -
n on e (29). A solution of benzoyl choride (1.94 g, 13.8 mmol)
in CH2Cl2 (5 mL) was slowly added, at room temperature, to
a stirred suspension of anhydrous AlCl3 (3.98 g, 29.8 mmol)
in CH2Cl2 (25 mL). After 10 min, a solution of (4-methoxyphen-
yl)(1H-pyrrol-3-yl)methanone (3) (2.5 g, 12.44 mmol) in CH2-
Cl2 (5 mL) was added dropwise at room temperature, and the
resulting mixture was stirred for 30 min. The reaction was
quenched with ice and water, and the product was extracted
with CH2Cl2 (2 × 50 mL). The combined organic extracts were
washed with saturated NaCl solution, dried over NaSO4, and
evaporated under reduced pressure. The residue was flash
chromatographed with EtOAc/petroleum ether (4:1) followed
by recrystallization from toluene/petroleum ether to provide
the title compound (2.28 g, 60%): mp 165-166 °C; IR (Nujol)
3250, 1625 cm-1; 1H NMR (CDCl3) δ 3.85 (s, 3H, (phenyl)OCH3),
6.80-7.10 (m, 2H, pyrrolyl-3,5H), 7.20-8.10 (m, 9H, (bis)phenyl-
H), 10.70 (br s, 1H, pyrrolyl-1H). Anal. (C19H15NO3) C, H, N.
[3-(Bip h en yl-4-ca r bon yl)p yr r ol-1-yl]a cetic a cid eth yl
ester (37): mp 96-97 °C; Anal. (C21H19NO3) C, H, N.
[3-(Naph th alen e-1-car bon yl)pyr r ol-1-yl]acetic acid eth -
yl ester (38): mp 74-75 °C; Anal. (C19H17NO3) C, H, N.
[3-(Naph th alen e-2-car bon yl)pyr r ol-1-yl]acetic acid eth -
yl ester (39): mp 72-74 °C; Anal. (C19H17NO3) C, H, N.
[3-(1-P h en yl-1H -p yr r ol-3-ca r b on yl)p yr r ol-1-yl]a cet ic
a cid eth yl ester (40): viscous oil; 1H NMR (CDCl3) δ 1.30 (t,
3H, CH2CH3, J ) 4.8 Hz), 4.25 (q, 2H, CH2CH3, J ) 4.8 Hz),
4.65 (s, 2H, CH2CO2), 6.65-6.95 (m, 4H, pyrrolyl-4,5H and
(phenyl)pyrrolyl-4,5H), 7.05-7.15 (m, 1H, pyrrolyl-2H), 7.40 (s,
5H, phenyl-H), 7.65-7.80 (m, 1H, (phenyl)pyrrolyl-2H).
[3-(4-P yr r ol-1-yl-ben zoyl)p yr r ol-1-yl]a cetic a cid eth yl
ester (41): mp 81 °C; Anal. (C19H18N2O3) C, H, N.
[3-(1-Meth yl-1H-in dol-3-car bon yl)pyr r ol-1-yl]acetic acid
1
eth yl ester (42): viscous oil; H NMR (CDCl3) δ 1.20 (t, 3H,
CH2CH3, J ) 4.8 Hz), 3.70 (s, 3H, (indolyl)CH3), 4.20 (q, 2H, CH2-
CH3, J ) 4.8 Hz), 4.60 (s, 2H, CH2CO2), 6.50-6.70 (m, 2H,
pyrrolyl-4,5H), 7.10-7.30 (m, 4H, pyrrolyl-2H and indolyl-
5,6,7H), 7.60 (s, 1H, indolyl-2H), 8.15-8.40 (m, 1H, indolyl-
4H).
[3-(Ben zofu r a n -5-ca r bon yl)p yr r ol-1-yl]a cetic a cid eth -
yl ester (43): mp 74-75 °C; Anal. (C17H15NO4) C, H, N.
[3-(2,3-Dih ydr o-ben zofu r an -5-car bon yl)pyr r ol-1-yl]ace-
tic a cid eth yl ester (44): mp 91-92 °C; Anal. (C17H17NO4)
C, H, N.
(3-P h en yla cetylp yr r ol-1-yl)a cetic a cid eth yl ester (45):
mp 61-62 °C; Anal. (C16H17NO3) C, H, N.
[3-(3-Ch lor oben zoyl)p yr r ol-1-yl]a cetic a cid eth yl ester
(46): mp 59-60 °C; Anal. (C15H14NO3Cl) C, H, N.
(2,4-Diben zoylp yr r ol-1-yl)a cetic a cid eth yl ester (47):
mp 85-86 °C; Anal. (C22H19NO4) C, H, N.
[2-Ben zoyl-4-(4-m eth oxyben zoyl)pyr r ol-1-yl]acetic acid
eth yl ester (48): mp 105-106 °C; Anal. (C23H21NO5) C, H, N:
calcd, N 3.58; found 3.99.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Eth yl
Acetic Acid Ester Der iva tives 31-49. To a cold (ice bath),
stirred, and under a nitrogen atmosphere mixture of the
corresponding either (aroyl-1H-pyrrol-3-yl)methanones (1-
11;32a 14, 19, 23, 25), or 2-phenyl-1-(1H-pyrrol-3-yl)ethanone
(12),32b or (5-aroyl-1H-pyrrol-3-yl)arylmethanones (28,39 29,
3039) (15 mmol), ethyl bromoacetate (4.05 g, 24 mmol), and
[tris[2-(methoxyethoxy)ethyl]amine [TDA-1] (0.75 mL, 2.4
mmol) in toluene (225 mL) was added NaH (50% dispersion
in mineral oil) (1.05 g, 22.5 mmol). The resulting mixture was
stirred at room temperature for 24-48 h. After this period, it
was poured into a stirred, ice cold, mixture of Et2O (150 mL)
and 5% HCl (150 mL). The two phases were separated, and
the aqueous phase was extracted with Et2O (2 × 100 mL). The
combined organic extracts were washed with 10% NaHCO3 (2
× 100 mL) and saturated NaCl solution and dried (K2CO3).
The solvents were evaporated under reduced pressure, and the
residue was flash chromatographed with a suitable mixture
of EtOAc/petroleum ether followed (if solid material) by
recrystallization from either Et2O/petroleum ether or CH2Cl2/
petroleum ether (36, 41, 47). The yields ranged between 40%
to 80%.
[2,4-bis-(4-Meth oxyben zoyl)p yr r ol-1-yl]a cetic a cid eth -
yl ester (49): mp 112 °C; Anal. (C24H23NO6) C, H, N.
(3-Ben zylp yr r ol-1-yl)a cetic Acid Eth yl Ester (52). To
a stirred, at room temperature, solution of (3-benzoylpyrrol-
1-yl)acetic acid ethyl ester (51)28 (2.87 g, 10 mmol) in 1,2-
dichloroethane (50 mL) were added zinc iodide (4.79 g, 15
mmol) and sodium cyanoborohydride (4.7 g, 75 mmol). The
reaction mixture was stirred at room temperature for 20 h. It
was then filtered through Celite. The Celite was washed with
dichloromethane (100 mL). The combined filtrates were dried
over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was flash chromatographed with petro-
leum ether/EtOAc (15:1) to provide the title compound (1.71
g, 63%) as a viscous oil: IR (neat) 1740 cm-1; 1H NMR (CDCl3)
δ 1.25 (t, 3H, CH2CH3, J ) 4.8 Hz), 3.80 (s, 2H, (phenyl)CH2),
4.20 (q, 2H, CH2CH3, J ) 4.8 Hz), 4.55 (s, 2H, CH2CO2), 6.00-
6.10 (m, 1H, pyrrolyl-4H), 6.25-6.40 (m, 1H, pyrrolyl-2H),
6.45-6.65 (m, 1H, pyrrolyl-5H), 7.25 (s, 5H, phenyl-H).
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Acetic
Acid Der iva tives 54-56, 58-70, a n d 72-75. A mixture of
the previously described ethyl ester derivatives (6 mmol),
dioxane (100 mL), and 5% NaOH solution (100 mL) was stirred
at room temperature for 1 h. After this period, it was
concentrated to half of its volume, H2O (100 mL) was added,
and the mixture was cooled (ice bath) and acidified with
concentrated HCl. The formed precipitate was collected by
filtration, and the filtrate was extracted with CHCl3 (2 × 100
mL). The organic phase was washed with saturated NaCl
solution and evaporated under reduced pressure. The residue
was combined with the precipitate and recrystallized from
toluene/petroleum ether, except for compound 70. This acid
was purified by flash chromatography EtOAc/EtOH (9:1)
followed by recrystallization from toluene/petroleum ether. The
yields of the target acids ranged from 68 to 97%.
[3-(4-Meth ylben zoyl)p yr r ol-1-yl]a cetic a cid eth yl ester
(31): mp 74-75 °C; IR (Nujol) 1740, 1620 cm-1 1H NMR
;
(CDCl3) δ 1.25 (t, 3H, CH2CH3, J ) 4.8 Hz), 2.40 (s, 3H,
(phenyl)CH3), 4.20 (q, 2H, CH2CH3, J ) 4.8 Hz), 4.65 (s, 2H, CH2-
CO2), 6.65-6.80 (m, 2H, pyrrolyl-4,5H), 7.10-7.35 (m, 3H,
pyrrolyl-2H and phenyl-3,5H), 7.70 (d, 2H, phenyl-2,6H, J )
6.7 Hz). Anal. (C16H17NO3) C, H, N.
[3-(4-ter t-Bu tylben zoyl)p yr r ol-1-yl]a cetic a cid eth yl
ester (32): mp 89-90 °C; Anal. (C19H23NO3) C, H, N.
[3-(4-Meth oxyben zoyl)p yr r ol-1-yl]a cetic a cid eth yl es-
ter (33): mp 77-78 °C; Anal. (C16H17NO4) C, H, N.
[3-(4-Ch lor oben zoyl)p yr r ol-1-yl]a cetic a cid eth yl ester
(34): mp 89-90 °C; Anal. (C15H14NO3Cl) C, H, N.
[3-(4-Tr iflu or om et h ylb en zoyl)p yr r ol-1-yl]a cet ic a cid
eth yl ester (35): mp 118-119 °C; Anal. (C16H14NO3F3) C, H,
N.
[3-(4-Meth ylben zoyl)p yr r ol-1-yl]a cetic a cid (54): mp
159-160 °C; IR (Nujol) 3300-2500, 1720, 1610 cm-1; 1H NMR
(CDCl3-DMSO-d6) δ 2.40 (s, 3H, (phenyl)CH3), 4.65 (s, 2H, CH2-
CO2), 6.40 (br s, 1H, CO2H), 6.55-6.80 (m, 2H, pyrrolyl-4,5H),
[3-(4-Nitr oben zoyl)p yr r ol-1-yl]a cetic a cid eth yl ester
(36): mp 126-127 °C; Anal. (C15H14N2O5) C, H, N.

424 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3
Nicolaou and Demopoulos
7.10-7.35 (m, 3H, phenyl-3,5H, and pyrrolyl-2H), 7.70 (d, 2H,
phenyl-2,6H, J ) 7.0 Hz). Anal. (C14H13NO3) C, H, N.
[3-(4-ter t-Bu tylben zoyl)p yr r ol-1-yl]a cetic a cid (55): mp
155-156 °C; Anal. (C17H19NO3) C, H, N.
[3-(4-Meth oxyben zoyl)p yr r ol-1-yl]a cetic a cid (56): mp
172-173 °C; Anal. (C14H13NO4) C, H, N.
In Vitr o P r otein Glyca tion Assa y. The assay was per-
formed as previously described.22b,44 It involved incubation of
bovine serum albumin (BSA, fraction V, essentially fatty acid
free) with fructose for 28 days. The test compounds 64, 65,
74, 75, and trolox (reference) were dissolved in water in the
form of their potassium salts. Results are shown in Table 2.
[3-(4-Ch lor oben zoyl)p yr r ol-1-yl]a cetic a cid (58): mp
175-176 °C; Anal. (C13H10NO3Cl) C, H, N.
[3-(4-Tr iflu or om et h ylb en zoyl)p yr r ol-1-yl]a cet ic a cid
(59): mp 169-170 °C; Anal. (C14H10NO3F3) C, H, N.
[3-(4-Nitr oben zoyl)pyr r ol-1-yl]acetic acid (60): mp 185-
186 °C; Anal. (C13H10N2O5) C, H, N.
[3-(Bip h en yl-4-ca r bon yl)p yr r ol-1-yl]a cetic a cid (61):
mp 182-183 °C; Anal. (C19H15NO3) C, H, N.
[3-(Naph th alen e-1-car bon yl)pyr r ol-1-yl]acetic acid (62):
mp 178-180 °C; Anal. (C17H13NO3) C, H, N.
[3-(Naph th alen e-2-car bon yl)pyr r ol-1-yl]acetic acid (63):
mp 196-197 °C; Anal. (C17H13NO3) C, H, N.
[3-(1-P h en yl-1H -p yr r ol-3-ca r b on yl)p yr r ol-1-yl]a cet ic
a cid (64): mp 168 °C; Anal. (C17H14N2O3) C, H, N.
[3-(4-P yr r ol-1-yl-ben zoyl)p yr r ol-1-yl]a cetic a cid (65):
mp 217-218 °C; Anal. (C17H14N2O3) C, H, N.
[3-(1-Meth yl-1H-in dol-3-car bon yl)pyr r ol-1-yl]acetic acid
(66): mp 222-223 °C; Anal. (C16H14N2O3‚0.48CHCl3) C, H, N.
[3-(Ben zofu r a n -5-ca r bon yl)p yr r ol-1-yl]a cetic a cid (67):
mp 173-174 °C; Anal. (C15H11NO4) C, H, N.
[3-(2,3-Dih yd r oben zofu r a n -5-ca r bon yl)p yr r ol-1-yl]a ce-
tic a cid (68): mp 195-196 °C; Anal. (C15H13NO4) C, H, N.
(3-P h en yla cetylp yr r ol-1-yl)a cetic a cid (69): mp 153-
154 °C; Anal. (C14H13NO3‚0.1H2O) C, H, N.
Ack n ow led gm en t. This work was supported by the
grant PENED99ED427 from the General Secretariat of
Research and Technology of Greece. Special thanks are
addressed to Najlaa Zaher (M.Sc.) and Dr. Antonis
Gavalas for expert technical assistance.
Refer en ces
(1) (a) King, H.; Aubert, R. E.; Herman, W. H. Global Burden of
Diabetes, 1995-2025: Prevalence, Numeric Estimates, and
Projections. Diabetes Care 1998, 21, 1414-1431. (b) Haigh, D.;
Avandia-From Molecule to Market for Type 2 Diabetes. Abstracts
of Papers; 223rd National Meeting of the American Chemical
Society, Apr 7-11, 2002, Orlando, FL; American Chemical
Society: Washington, DC, 2002; 132-MEDI.
(2) Costantino, L.; Rastelli, G.; Vianello, P.; Cignarella, G.; Barlocco,
D. Diabetes Complications and their Potential Prevention:
Aldose Reductase Inhibition and other Approaches. Med. Res.
Rev. 1999, 19, 3-23.
(3) (a) Kangas, T.; Aro, S.; Koivisto, V. A.; Salinto, M.; Laakso, M.;
Reunanen, A. Structure and Costs of Health Care of Diabetic
Patients in Finland. Diabetes Care 1996, 19, 191-197. (b)
Parving, H. H. Strategies to Reduce the Burden of Diabetic
Complications. Diabetologia 1997, 40, B9-B10.
(4) The Diabetes Control and Complications Trial Research Group.
The Effect of Intensive Treatment of Diabetes on the Develop-
ment and Progression of Long-Term Complications in Insulin-
Dependent Diabetes Mellitus. N. Engl. J . Med. 1993, 329, 977-
986.
(3-Ben zylp yr r ol-1-yl)a cetic a cid (70): mp 84-85 °C;
Anal. (C13H13NO2) C, H, N.
(5) (a) Okhubo, Y.; Kishikawa, H.; Araki, E.; Miyata, T.; Isami, S.;
Motoyoshi, S.; Kojima, Y.; Furugoshi, N.; Shichiri, M. Intensive
Insulin Therapy Prevents the Progression of Diabetic Microvas-
cular Complications in J apanese Patients with Non-Insuline-
Dependent Diabetes Mellitus: A Randomized Prospective 6-Year
Study. Diabetes Res. Clin. Pract. 1995, 28, 103-117. (b) Ameri-
can Diabetes Association. Implications of the Diabetes Control
and Complications Trial. Diabetes Care 1998, 21, S88-90.
(6) Barrett-Connor, E.; Wingard, D. L. “Normal” Blood Glucose and
Coronary Risk. Br. Med. J . 2001, 322, 5-6.
[3-(3-Ch lor oben zoyl)p yr r ol-1-yl]a cetic a cid (72): mp
151-152 °C; Anal. (C13H10NO3Cl) C, H, N: calcd, C 59.22;
found 58.78.
(2,4-Diben zoylp yr r ol-1-yl)a cetic a cid (73): mp 173-174
°C; Anal. (C20H15NO4) C, H, N.
[2-Ben zoyl-4-(4-m eth oxyben zoyl)pyr r ol-1-yl]acetic acid
(74): mp 158-160 °C; Anal. (C21H17NO5) C, H, N.
[2,4-bis-(4-Meth oxyben zoyl)pyr r ol-1-yl]acetic acid (75):
mp 200 °C; 1H NMR (CDCl3-DMSO-d6) δ 3.90 (s, 6H,
(bis-phenyl)OCH3), 5.10 (s, 2H, CH2CO2), 6.80-7.05 (m, 5H,
pyrrolyl-3H and (bis)phenyl-3,5H), 7.15 (s, 1H, pyrrolyl-5H), 7.60
(s, 1H, CO2H) 7.80(d, 4H, (bis)phenyl-2,6H, J ) 7.1 Hz). Anal.
(C22H19NO6) C, H, N.
(7) Carrington, A. L.; Litchfield, J . E. The Aldose Reductase
Pathway and Nonenzymatic Glycation in the Pathogenesis of
Diabetic Neuropathy: A Critical Review for the End of the 20th
Century. Diabetes Rev. 1999, 7, 275-299.
(8) Stout, R. W. Insulin and Atheroma-An Update. Lancet 1987, 1
(Iss. 8541), 1077-1079.
[3-(4-Hyd r oxyben zoyl)p yr r ol-1-yl]a cetic a cid (57). To
a solution of ester 33 (2.6 g, 9 mmol) in dry CH2Cl2 (35 mL) at
-80 °C under a nitrogen atmosphere was added dropwise a
solution of boron tribromide (7.5 g, 30 mmol) in dry CH2Cl2
(40 mL). When the addition was completed, the reaction
mixture was stirred at room-temperature overnight. Then, it
was quenched with a mixture of 10% HCl (50 mL) and EtOAc
(50 mL), the two phases were separated, and the aqueous was
extracted with EtOAc. The combined organic extracts were
washed with saturated NaCl solution, dried over Na2SO4, and
concentrated under reduced pressure. The hydrolysis, work
up and purification was similar to that described above in the
general procedure, to provide the title compound (1.33 g,
60%): mp 188 °C; IR (Nujol): 3420, 3300-2500, 1700, 1610
(9) Friedman, E. A. Advanced Glycosylated End Products and
Hyperglycemia in the Pathogenesis of Diabetic Complications.
Diabetes Care, 1999, 22 (Suppl. 2), B65-71.
(10) Oates, P. J .; Mylari, B. L. Aldose Reductase Inhibitors: Thera-
peutic Implications for Diabetic Complications. Expert Opin.
Investig. Drugs 1999, 8, 2095-2119.
(11) (a) Tomlinson, D. R.; Stevens, E. J .; Diemel, L. T. Aldose
Reductase Inhibitors and their Potential for the Treatment of
Diabetic Complications. Trends Pharmacol. Sci. 1994, 15, 293-
297. (b) Nishimura, C. Aldose Reductase in Glucose Toxicity: A
Potential Target for the Prevention of Diabetic Complications.
Pharmacol. Rev. 1998, 50, 21-33. (c) Mistry, K. P.; Beyer-Mears,
A.; Diecke, F. P. J . Mechanisms for D-Glucose Inhibition of myo-
Inositol Influx into Rats Lens. Diabetes 1993, 42, 1737-1744.
(d) Stevens, M. J .; Lattimer, S. A.; Kamijo, M.; Van Huysen, C.;
Sima, A. A. F.; Greene, D. A. Osmotically-Induced Nerve Taurine
Depletion and the Compatible Osmolyte Hypothesis in Experi-
mental Diabetic Neuropathy in the Rat. Diabetologia 1993, 36,
608-614. (e) De Luca, G.; Calpona, P. R., Caponetti, A.; Romano,
G.; Di Benedetto A.; Cucinotta, D.; Di Giorgio, R. M. Taurine
and Osmoregulation: Platelet Taurine Content, Uptake, and
Release in Type 2 Diabetic Patients. Metab.-Clin. Exp. 2001, 50,
60-64.
cm-1 1H NMR (CDCl3-DMSO-d6): δ 4.75 (s, 2H, CH2CO2),
;
6.50-6.70 (m, 2H, pyrrolyl-4,5H), 6.85 (d, 2H, phenyl-3,5H, J
) 6.7 Hz), 7.25-7.45 (m, 1H, pyrrolyl-2H), 7.60-7.85 (m, 4H,
phenyl-2,6H, CO2H, and (phenyl)OH, after adition of D2O changes
to d, 2H, δ ) 7.70, J ) 6.7 Hz). Anal. (C13H11NO4) C, H, N.
In Vitr o Ald ose Red u cta se En zym e Assa y. The test
compounds 54-75, (3-benzoylpyrrol-1-yl)acetic acid (I), (2-
benzoylpyrrol-1-yl)acetic acid (II), trolox (6-hydroxy-2,5,7,8-
tetramethyl-chroman-2-carboxylic acid), and sorbinil (refer-
ence) were dissolved in 0.2 M NaHCO3. Lenses were quickly
removed from Fischer-344 rats of both sexes following eutha-
nasia, and enzyme preparation and assay were performed as
previously described.38b All experiments were performed in
triplicate. Results are shown in Table 1.
(12) Kawasaki, Y.; Fujii, J .; Miyazawa, N.; Hoshi, A.; Okado, A.; Tano,
Y.; Taniguchi, N. Specific Detections of the Early Process of the
Glycation Reactions By Fructose and Glucose in Diabetic Rat
Lens. FEBS Lett. 1998, 441, 116-120.
(13) (a) Wolff, S. P.; J iang, Z. Y.; Hunt, J . V. Protein Glycation and
Oxidative Stress in Diabetes Mellitus and Aging. Free Radic.
Biol. Med. 1991, 10, 339-352. (b) Takagi, Y.; Kashiwagi, A.;
Tanaka, Y.; Asahina, T.; Kikkawa, R.; Shigeta, Y. Significance
of Fructose-Induced Protein Oxidation and Formation of Ad-
vanced Glycation End Product. J . Diabetes Complicat. 1995, 9,

Pyrrol-1-ylacetic Acid Aldose Reductase Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3 425
87-91. (c) Hayase, F.; Shibuya, T.; Sato, J .; Yamamoto, M.
Effects of Oxygen and Transition Metals on the Advanced
Maillard Reaction of Proteins with Glucose. Biosci. Biotech.
Biochem. 1996, 60, 1820-1825.
(28) Demopoulos, V. J .; Rekka, E. Isomeric Benzoylpyrroleacetic
Acids: Some Structural Aspects for Aldose Reductase Inhibitory
and Antiinflammatory Activities. J . Pharm. Sci. 1995, 84, 79-
82.
(29) Hajduk, P. J .; Bures, M.; Praestgaard, J .; Fesik, S. W. Privileged
Molecules for Protein Binding Identified from NMR-Based
Screening. J . Med. Chem. 2000, 43, 3443-3447.
(14) (a) Hunt, J . V.; Wolff, S. P. Oxidative Glycation and Free Radical
Production: A Causal Mechanism of Diabetic Complications.
Free Rad. Res. Commun. 1991, 12-13, 115-123.
(30) Lehue´de´, J .; Fauconneau, B.; Barrier, L.; Ourakow, M.; Piriou,
A.; Vierfond, J -M. Synthesis and Antioxidant Activity of new
Tetraarylpyrroles. Eur. J . Med. Chem. 1999, 34, 991-996.
(31) Roberfroid, M. B.; Viehe, H. G.; Remacle, J . Free Radicals in
Drug Research. In Advances in Drug Research; Testa, B., Ed.;
Academic Press Limited: London, 1987; vol. 16; pp 15-19.
(32) (a) Nicolaou, I.; Demopoulos, V. J . A Study of the Friedel-Crafts
Acylation of 1-Benzenesulfonyl-1H-pyrrole in the Preparation
of 3-Aroylpyrroles. J . Heterocycl. Chem. 1998, 35, 1345-1348.
(b) Greenhouse, R.; Ramrez, C.; Muchowski, J . M. Synthesis of
Alkylpyrroles by the Sodium Borohydride Reduction of Acylpyr-
roles. J . Org. Chem. 1985, 50, 2961-2965. (c) Ketcha, D. M.;
Gribble, G. W. A Convenient Synthesis of 3-Acylindoles via
Friedel-Crafts Acylation of 1-(Phenylsulfonyl)indole. A New
Route to Pyridocarbazole-5,11-quinones and Ellipticine. J . Org.
Chem. 1985, 50, 5451-5457.
(33) Entwistle, I. D.; J ackson, A. E.; J ohnstone, A. W.; Telford, R. P.
Reduction of Nitro-Compounds. J . Chem. Soc., Perkins Trans. 1
1977, 443-447.
(34) Tembo, O. N.; Dallemagne, P.; Rault, S.; Robba, M. An Efficient
Synthesis of New Phenylpyrrolizine and Phenylpyrrolopyrazine
Derivatives. Heterocycles 1993, 36, 2129-2137.
(35) Leysen, F. Y.; Ottenheijm, H. C. J . A Facile Synthesis of
N-Substituted Pyrroles. Synth. Commun. 1995, 25, 1857-1861.
(36) Cardinaud, I.; Gueiffier, A.; Debouzy, J -C.; Milhared, J -C.;
Chapat, J -P. Synthesis of Pyrroloquinoline and Pyrrolonaph-
thiridine by an Intramolecular Cyclisation Reaction. Heterocycles
1993, 36, 2513-2522.
(37) Chan, T. H.; Lee, S. D. 1,4-Dichloro-1,4-dimethoxybutane as a
Mild Reagent for the Conversion of Primary Amines to Pyrroles.
Synthesis of a Pyrrole Compound from Tobacco. J . Org. Chem.
1983, 48, 3059-3061.
(38) (a) Dunn, J . P.; Ackerman, N. A.; Tomolonis, A. J . Analgetic and
Antiinflammatory 7-Aroylbenzofuran-5-ylacetic Acids and 7-Aroyl-
benzothiophene-5-ylacetic Acids. J . Med. Chem. 1986, 29, 2326-
2329. (b) Zaher, N; Nicolaou, I; Demopoulos, V. J . Pyrrolylben-
zothiazole Derivatives as Aldose Reductase Inhibitors. J . Enzyme
Inhib. Med. Chem. 2002, 17, 131-135.
(39) Cadamuro, S.; Degani, I.; Dagnera, S.; Fachi, R.; Gatti. A.;
Piscopo. L. General Methods for Synthesizing 2,4-Diacylpyrroles
and their Precursors Containing One or Two Masked Acyl
Groups. J . Chem. Soc., Perkin Trans. 1 1993, 273-283.
(40) Lau, C. K.; Dufrene, C.; Belanger, P. C.; Pietre, S.; Scheigetz J .
Reductive Deoxygenation of Aryl Aldehydes and Ketones and
Benzylic Allylic and Tertiary Alcohols by ZnI2-NaCNBH3. J .
Org. Chem. 1986, 51, 3038-3043.
(41) Bell, Malcolm Rie (Sterling Drug Inc.) Ger. Offen. 1908541 (Cl.
C 07d, A 61k), 18 Sep 1969, US Appl. Feb 1968; 1-(Carboxy-
alkyl)indoles. Chem. Abstr. 1970, 72, 66807m.
(42) McOmie, J . F.; Watts, M. L.; West, D. E. Demethylation of Aryl
Methyl Ethers by Boron Tribromide. Tetrahedron 1968, 24,
2289-2292.
(43) Olah, G. A.; Narany, S. C.; Gupta, B. J . B.; Mulhotra, R.
Synthetic Methods and Reactions. Transformations with Chlo-
rotrimethylsilane/Sodium Iodide, a Convenient in situ Iodotri-
methylsilane Reagent. J . Org. Chem. 1979, 44, 1247-1251.
(44) Anagnostou, C.; Nicolaou, I.; Demopoulos, V. J . Synthesis of [5-(4-
Pyrrol-1-yl-benzoyl)-1H-pyrrol-2-yl)]-acetic Acid and In Vitro
Study of its Inhibitory Activity on Aldose Reductase Enzyme and
on Protein Glycation. Pharmazie 2002, 57, 535-537.
(15) Constantino, L.; Rastelli, G.; Gamberini, M. C.; Vinson, J . A.;
Bose, P.; Iannone, A.; Staffieri, M.; Antolini, L.; Del Corso, A.;
Mura, U.; Albasini, A. 1-Benzopyran-4-one Antioxidants as
Aldose Reductase Inhibitors. J . Med. Chem. 1999, 42, 1881-
1893.
(16) Nakamura, N.; Obayashi, H.; Fujii, M.; Fukui, M.; Yoshimori,
K.; Ogata, M.; Hasegawa, G.; Shigeta, H.; Kitagawa, Y.; Yoshika-
wa, T.; Kondo, M.; Ohta, M.; Nishimura, M.; Nishinaka, T.;
Nishimura, C. Y. Induction of Aldose Reductase in Cultured
Human Microvascular Endothelial Cells by Advanced Glycation
End Products. Free Radic. Biol. Med. 2000, 29, 17-25.
(17) Oberley, L. W. Free Radicals and Diabetes. Free Radic. Biol.
Med. 1988, 5, 113-124.
(18) Costantino, L.; Rastelli, G.; Gamberini, M. C.; Barlocco, D.
Pharmacological Approaches to the Treatment of Diabetic
Complications. Expert Opin. Ther. Patents 2000, 10, 1245-1262.
(19) Strupczewski, J . D.; Ellis, D. B. To Market, To Market-1992. In
Annual Reports in Medicinal Chemistry; Bristol, J . A., Ed.;
Academic Press Inc.: San Diego, 1993; vol. 28; p 330.
(20) (a) Banditelli, S.; Boldrini, E.; Vilardo, P. G.; Cecconi, I.;
Cappiello, M.; dal Monte, M.; Marini I.; del Corso, A.; Mura, U.
A New Approach Against Sugar Cataract Through Aldose
Reductase Inhibitors. Exp. Eye Res. 1999, 69, 533-538. (b)
Nakamura, J .; Kasuya, Y.; Hamad, Y.; Nakshima, E.; Naruse,
K.; Yasuda, Y.; Kato, K.; Hotta, N. Glucose-Induced Hyperpro-
liferation of Cultured Rat Aortic Smooth Muscle Cells through
Polyol Pathway Hyperactivity. Diabetologia 2001, 44, 480-487.
(c) Murata, M.; Ohta, N.; Sakurai, S.; Alam, S.; Tsai, J . Y.; Kador,
P. F.; Sato, S. The Role of Aldose Reductase in Sugar Cataract
Formation: Aldose Reductase Plays a Key Role in Lens Epithe-
lial Cell Death (Apoptosis). Chem.-Biol. Interact. 2001, 130 (1-3
Special Issue S1), 617-625.
(21) (a) Hamada, Y.; Nakamura, J .; Naruse, K.; Komori, T.; Kato,
K.; Kasuya, Y.; Nagai, R.; Horiuchi, S.; Hotta, N. Epalrestat,
an Aldose Reductase Inhibitor, Reduces the Levels of N-Epsilon-
(Carboxymethyl)Lysine Protein Adducts and their Precursors in
Erythrocytes from Diabetic Patients. Diabetes Care 2000, 23,
1539-1544. (b) Nakayama, M.; Nakamura, J .; Hamada, J .;
Chaya, S.; Mizubayashi, R.; Yasuda, Y.; Kamiya, K.; Koh, N.;
Hotta, N. Aldose Reductase Inhibition Ameliorates Pupillary
Light Reflex and F-Wave Latency in Patients with Mild Diabetic
Neuropathy. Diabetes Care 2001, 24, 1093-1098. (c) J ohnson,
B. F.; Law, G.; Nesto, R.; Pfeifer, M.; Slater, W.; Vinic, A.;
Wackers, F.; Young, L. Aldose Reductase Inhibitor Zopolrestat
Improves Systolic Function in Diabetics. Diabetes, 1999, 48 (Iss.
S1), 574. (d) Hotta, N.; Ishii, J .; Sakamoto, N. Effects of
Fidarestat, an Aldose Reductase Inhibitor, on Diabetic Periph-
eral Neuropathy. A 52-Week Placebo-Controlled Double-Blind-
Study. Diabetes 2000, 49 (Iss. S1), 142.
(22) (a) Kawabata, T.; Packer, L. Alpha-Lipoate Can Protect Against
Glycation of Serum Albumin, but not Low-Density Lipoprotein.
Biochem. Biophys. Res. Commun. 1994, 203, 99-104. (b) Stefek,
M.; Krizanova, L.; Trnkova, Z. Oxidative Modification of Serum
Albumin in an Experimental Glycation Model of Diabetes
Mellitus In Vitro: Effect of the Pyridoindole Antioxidant Sto-
badine. Life Sci. 1999, 65, 1995-1997.
(23) Vinson, J . A.; Howard, T. B., III. Inhibition of Protein Glycation
and Advanced Glycation End Products by Ascorbic Acid and
other Nutrients. J . Nutr. Biochem. 1996, 7, 659-663.
(24) Edelstein, D.; Brownlee, M. Mechanistic Studies of Advanced
Glycation End Product Inhibition by Aminoguanidine. Diabetes
1992, 41, 26-29.
(25) Miyata, T.; Ueda, Y.; Asahi, K.; Izuhara, Y.; Inagi, R.; Saito, A.;
Destrihou, C. V.; Kurokawa, K. Mechanism of the Inhibitory
Effect of OPB-9195 [(()-2-Isopropylidenehydrazono-4-oxo-thia-
zolidin-5-ylacetanilide] on Advanced Glycation End-Product and
Advanced Lipoxidation End-Product Formation. J . Am. Soc.
Nephrol. 2000, 11, 1719-1725.
(26) (a) Cunningham, J . J . The Glucose/Insulin System and Vitamin
C: Implications in Insulin-Dependent Diabetes Mellitus. J . Am.
Coll. Nutr. 1998, 17, 105-108. (b) Tutuncu, N. B.; Bayraktar,
M.; Varli, K. Reversal of Defective Nerve Conduction with
Vitamin E Supplementation in Type 2 Diabetes-A Preliminary
Study. Diabetes Care 1998, 21, 1915-1918.
(45) Gui, T.; Tanimoto, T.; Kokai, Y.; Nishimura, C. Presence of a
Closely-Related Subgroup in the Aldo-Ketoreductase Family of
the Mouse. Eur. J . Biochem. 1995, 227, 448-453.
(46) Del Corso, A.; Costantino, L; Rastelli, G.; Buono, F.; Mura, U.
Aldose Reductase does Catalyse the Reduction of Glyceraldehyde
through a Stoichiometric Oxidation of NADPH. Exp. Eye Res.
2000, 71, 515-521.
(47) (a) Sestanj, K.; Bellini, F.; Fung, S.; Abraham, N.; Treasurywala,
A.; Humber, L.; Simard-Duquesne, N.; Dvornik, D. N-[[5-(Tri-
fluoromethyl)-6-methoxy-1-naphthalenyl]-N-methylglycine (Tol-
restat), a Potent, Orally Active Aldose Reductase Inhibitor. J .
Med. Chem. 1984, 27, 255-256. (b) Terashima, H.; Hama, K.;
Yamamoto, R.; Tsuboshima, M.; Kikkawa, R.; Hatanaka, I.;
Shigeta, Y. Effects of a New Aldose Reductase Inhibitor on
Various Tissues In Vitro. J . Pharmacol. Exp. Ther. 1984, 229,
226-230. (c) Mylari, B. L.; Larson, E. R.; Beyer, T. A.; Zem-
browski, W. J .; Aldinger, C. E.; Dee, M. F.; Siegel. T. W.;
Singleton. D. H. Novel Potent Aldose Reductase Inhibitors: 3,4-
Dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-
1-phthalazineacetic Acid (Zopolrestat) and Congeners. J . Med.
Chem. 1991, 34, 108-122. (d) Oka, M.; Matsumoto, Y.; Sug-
(27) (a) Tsuchida, K.; Nakamura, S.; Fujii, W.; Atsumi, T.; Kawata,
T.; Makita, Z.; Koike, T. Decrease of TGF-Beta and Type-IV
Collagen Production in Diabetic Nephropathy by a Novel AGE
Inhibitor OPB-9195. Diabetes 1998, 47 (Iss. S1), 503. (b) Singh,
R.; Barden, A.; Mori, T.; Beilin, L. Advanced Glycation End-
Products: a Review. Diabetologia 2001, 44, 129-146.

426 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3
iyama, S.; Tsuruta. N.; Matsushima. M. Potent Aldose
Reductase Inhibitor, (2S,4S)-6-Fluoro-2′,5′-dioxospiro[chroman-
4,4′-imidazolidine]-2-carboxamide (Fidarestat): Its Absolute
Configuraton and Interactions with the Aldose Reductase by
X-ray Crystallography. J . Med. Chem. 2000, 43, 2479-2483.
(48) ClogP Version 4.72, Daylight Chemical Information Systems Inc.,
(http://www.daylight.com/).
Nicolaou and Demopoulos
A
Press: Oxford, 1985; pp 76-79.
(50) SPARTAN SGI Version 5.1.3 OpenGL, Wavefunction, Inc., 18401
Von Karman Avenue, Suite 370, Irvine, CA 92612.
(51) Llorens, O.; Perez, J . J . Toward the Design of Chemical Libraries
for Mass Screening Biased against Mutagenic Compounds. J .
Med. Chem. 2001, 44, 2793-2804.
(49) Katritzky, A. R. Handbook of Heterocyclic Chemistry; Pergamon
J M0209477