Synthesis of novel phenylacetic acid derivatives with halogenated benzyl subunit and evaluation as aldose reductase inhibitors

Article abstract of DOI:10.1016/j.ejps.2005.09.006

In the course of our ongoing studies several substituted benzyloxyphenylacetic acids were prepared. Comparison of their aldose reductase inhibition with the biological activity obtained for recently evaluated benzoic acid analogues revealed the critical role of a methylene spacer between the aromatic core and the acidic function. Starting from the most potent derivative (i.e. 5d, IC₅₀ = 20.9 μM) further structural modifications were performed and their influence on the inhibitory effect was established.

Full text of DOI:10.1016/j.ejps.2005.09.006

european journal of pharmaceutical sciences 2 7 ( 2 0 0 6 ) 188–193
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journal homepage: www.elsevier.com/locate/ejps
Synthesis of novel phenylacetic acid derivatives with
halogenated benzyl subunit and evaluation as aldose
reductase inhibitors
Dietmar Rakowitz∗, Andreas Gmeiner, Nicole Schro¨der, Barbara Matuszczak
Institute of Pharmacy, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
In the course of our ongoing studies several substituted benzyloxyphenylacetic acids were
prepared. Comparison of their aldose reductase inhibition with the biological activity
obtained for recently evaluated benzoic acid analogues revealed the critical role of a methy-
lene spacer between the aromatic core and the acidic function. Starting from the most potent
derivative (i.e. 5d, IC50 = 20.9 ␮M) further structural modifications were performed and their
influence on the inhibitory effect was established.
Received 9 June 2005
Received in revised form 19
September 2005
Accepted 22 September 2005
Available online 2 November 2005
© 2005 Elsevier B.V. All rights reserved.
Keywords:
Aldose reductase
Inhibitor
Enzyme inhibitors
Substituted phenylacetic acids
1.
Introduction
Using previously defined pharmacophore requirements
(Howard et al., 2004; Kinoshita et al., 2002; Podjarny et al.,
2004; Urzhumtsev et al., 1997; Wilson et al., 1993), we have
recently designed compounds of type I (see Fig. 1) as potential
ARIs. Initial studies (i.e. preparation and biological screening)
were done for derivatives with n = 0. Modifications included
the lipophilic (2-benzothiazolyl or benzyl residues) as well
as the hydrophilic moieties (carboxylic acid and bioisosters),
which represent the suggested pharmacophores. Moreover,
congeners bearing a substituted benzene core were also inves-
tigated. For these derivatives, the most interesting results
were obtained for compounds bearing a substituted benzyloxy
subunit (i.e. 4-bromobenzyloxy or 4-bromo-2-fluorobenzyloxy,
respectively) (Rakowitz et al., 2005a, 2005b).
In the course of diabetes mellitus, the enhanced glucose
metabolism via polyol pathway leads to an increased sorbitol
level. The accumulation of the latter causes diabetic compli-
cations such as nephropathy, neuropathy, retinopathy, and
cataracts. Thus, inhibition of the key enzyme aldose reduc-
tase (ALR 2) has received attention as a possible therapeutic
target, seeing that this safely prevents or stops the progres-
sion of these long-term complications. Since aldose reductase
inhibitors (ARIs) have no effect on plasma glucose level, there
is no risk of hypoglycemia. A variety of structurally diverse
compounds have been observed to inhibit ALR 2, these drugs
can be divided into two general classes containing either a car-
boxylic acid moiety or a spirohydantoin substructure, respec-
tively (Costantino et al., 1997). Nevertheless, to date none is
currently marketed for worldwide use due to lack of high effi-
cacy and selectivity or due to toxicity (Miyamoto, 2002).
In order to get further insight into structure–activity rela-
tionships, we now became interested in derivatives charac-
terised by a methylene spacer between the hydrophilic sub-
unit and the benzene core. Here we report on the synthesis
∗
Corresponding author.
0928-0987/$ – see front matter © 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejps.2005.09.006

european journal of pharmaceutical sciences 2 7 ( 2 0 0 6 ) 188–193
189
sphere of nitrogen. After stirring for 30 min at room tempera-
ture, the appropriate benzylbromide (4-bromobenzylbromide
or 4-bromo-2-fluorobenzylbromide) was added and stirring
was continued until tlc indicated no further conversion. Then,
the mixture was poured into cold water, the mixture was acid-
ified with 2N HCl and the product was extracted exhaustively
with diethyl ether. The organic layer was washed with water
and brine, dried over anhydrous sodium sulfate and evapo-
rated to dryness. The residue thus obtained was purified as
described in Table 1.
2.1.2. General procedure for the synthesis of carboxylic
acids of type 5 and 6
Fig. 1 – Model of potential ARIs of type I (characterised by
hydrophilic and lipophilic pharmacophores) in the active
site of the enzyme (the most important amino acids are
Trp20, Tyr48, His110, Trp111, Phe122, Leu300).
A solution of the appropriate ester (3a–f, 4a–b) in 5–10 ml of
ethanol was treated with 2N NaOH (1.2 equiv.) and stirred
overnight at room temperature. The solvent was then evap-
orated, the residue treated with a small amount of water
and the pH adjusted to 5 with 2N HCl. The reaction mix-
ture was extracted with ethyl acetate, the organic layer was
washed with water and brine, dried over anhydrous sodium
sulfate and evaporated to dryness under reduced pressure.
The residue thus obtained was purified as described in Table 2.
of such benzyloxyphenylacetic acids and their evaluation as
aldose reductase inhibitors.
2.1.3. General procedure for the synthesis of carboxylic
acids of type 7
2.
Materials and methods
A solution of 1.2 equiv. of trifluoroacetic anhydride in 4 ml of
dry dichloromethane was added dropwise to an ice-cooled
solution of the amino compound 6a or 6b (1.0 equiv.) in 5 ml
of dry dichloromethane. The reaction mixture was allowed to
warm to room temperature and stirred until complete con-
version (tlc control). Then, water was added and the pH was
adjusted to 7 with saturated NaHCO3 solution. The mixture
was extracted exhaustively with dichloromethane, the organic
layer was washed with water and brine, dried over anhydrous
sodium sulfate and evaporated to dryness. The residue thus
obtained was mixed with light petroleum to yield beige crys-
tals (Table 3).
2.1.
Chemistry
Melting points were determined with a Kofler hot-stage micro-
scope (Reichert) and are uncorrected. Infrared spectra (KBr
pellets) were recorded on a Mattson Galaxy Series FT-IR 3000
spectrophotometer. Mass spectra were obtained on a Finnigan
MAT SSQ 7000 spectrometer (EI, 70 eV or CI, 200 eV, reactant
gas: methane). All NMR spectra were recorded in DMSO-d6
or CDCl3 solution in 5 mm tubes at 30 ◦C on a Varian Gem-
ini 200 spectrometer (199.98 MHz for 1H) with the deuterium
signal of the solvent as the lock and TMS as internal stan-
dard. Chemical shifts are expressed in parts per million. Reac-
tions were monitored by tlc using Polygram® SIL G/UV254
(Macherey–Nagel) plastic-backed plates (0.25 mm layer thick-
ness). The yields given are not optimised. Light petroleum
refers to the fraction of bp 40–60 ◦C. Elemental analyses were
performed by Mag. J. Theiner, ‘Mikroanalytisches Laborato-
rium’, Faculty of Chemistry, University of Vienna, Austria and
the data for C, H (and N) are within 0.4% of the calculated
values.
4-Bromo-2-fluorobenzylbromide was synthesised by rad-
ical bromination of 4-bromo-2-fluorotoluene with N-bromo-
succinimide and a catalytic amount of azobisisobutyronitrile
in CCl4 as described in the literature (Quan et al., 1995). The
ethyl aminophenylacetates (compounds of type 2) were acces-
sible by reaction of the appropriate aminophenylacetic acid in
a mixture of EtOH, toluene, and concd. H2SO4 according to the
literature (Modrakowski et al., 2001). Compounds not listed
were commercial samples of good grade.
2.2.
Aldose reductase inhibitory assay
NADPH, d,l-glyceraldehyde, and dithiothreitol (DTT) were pur-
chased from Sigma Chemical Co. DEAE-cellulose (DE-52) was
obtained from Whatman. Sorbinil was a gift from Prof. Dr.
Luca Costantino, University of Modena (Italy) and was used as
standard [IC50 = 1.1 ( 0.3) ␮M]. All other chemicals were com-
mercial samples of good grade. Calf lenses for the isolation of
ALR 2 were obtained locally from freshly slaughtered animals.
The enzyme was purified by a chromatographic procedure as
previously described (Costantino et al., 1996). Briefly, ALR 2 was
released by carving the capsule and the frozen lenses were
suspended in potassium phosphate buffer pH 7 containing
5 mM DTT and stirred in an ice-cold bath for 2 h. The sus-
pension was centrifuged at 4000 rpm at 4 ◦C for 30 min and
the supernatant was subjected to ion exchange chromatog-
raphy on DE-52. Enzyme activity was assayed spectrophoto-
metrically on a Cecil Super Aurius CE 3041 spectrophotome-
ter by measuring the decrease in absorption of NADPH at
340 nm, which accompanies the oxidation of NADPH catal-
ysed by ALR 2. The assay was performed at 37 ◦C in a reaction
mixture containing 0.25 M potassium phosphate buffer pH 6.8,
2.1.1. General procedure for the O- or N-substitution to
prepare compounds of type 3 and 4
Powdered potassium carbonate was added to a solution of the
nucleophile (i.e. substituted phenol (1) or aniline (2), respec-
tively) in 5–10 ml of dry N,N-dimethylformamide under atmo-

190
european journal of pharmaceutical sciences 2 7 ( 2 0 0 6 ) 188–193
Table 1 – Data of compounds of type 3 and 4
No.
R, position, X, Rꢀ, formula (MW)
C2H5, 2, O, H, C17H17BrO3 (349.23)
Batch size purification properties
(yield) equiv.a
IR (cm−1), MS
(EI)
1H NMR
3a
2.78 mmol (2.0/1.0/4.0) cc with ‘A’
followed by recrystallization from
‘B’ (74%) colourless crystals mp
68–69 ◦C
1726, 348/350
(CDCl3) 7.54–7.47 (m, 2H, phenyl-H),
7.32–7.20 (m, 4H, phenyl-H), 6.99–6.86
(m, 2H, phenyl-H), 5.03 (s, 2H, CH2), 4.11
(q, J = 7.2 Hz, 2H, OCH2), 3.66 (s, 2H, CH2),
1.20 (t, J = 7.2 Hz, 3H, CH3)
3b
3c
C2H5, 2, O, F, C17H16BrFO3 (367.22)
C2H5, 3, O, H, C17H17BrO3 (349.23)
1.75 mmol (2.0/1.0/4.0) cc with ‘A’
followed by recrystallization from
‘B’ (72%) colourless crystals mp
58–60 ◦C
2.78 mmol (2.0/1.0/4.0) cc with ‘A’
(59%) colourless oil
1729, 366/368
1734, 348/350
(CDCl3) 7.45–7.21 (m, 5H, phenyl-H),
7.00–6.89 (m, 2H, phenyl-H), 5.10 (s, 2H,
CH2), 4.11 (q, J = 7.1 Hz, 2H, OCH2), 3.66
(s, 2H, CH2), 1.20 (t, J = 7.1 Hz, 3H, CH3)
(CDCl3) 7.54–7.47 (m, 2H, phenyl-H),
7.32–7.19 (m, 3H, phenyl-H), 6.90–6.82
(m, 3H, phenyl-H), 5.01 (s, 2H, CH2), 4.14
(q, J = 7.2 Hz, 2H, OCH2), 3.58 (s, 2H, CH2),
1.25 (t, J = 7.2 Hz, 3H, CH3)
3d
3e
C2H5, 3, O, F, C17H16BrFO3 (367.22)
1.75 mmol (2.0/1.0/2.0) cc with ‘A’
(65%) colourless oil
1734, 366/368
1735, 334/336
(CDCl3) 7.44–7.20 (m, 4H, phenyl-H),
6.93–6.84 (m, 3H, phenyl-H), 5.07 (s, 2H,
CH2), 4.15 (q, J = 7.2 Hz, 2H, OCH2), 3.58
(s, 2H, CH2), 1.25 (t, J = 7.2 Hz, 3H, CH3)
(CDCl3) 7.54–7.47 (m, 2H, phenyl-H), 7.29
(d, J = 8.6 Hz, 2H, phenyl-H), 7.19 (d,
J = 8.6 Hz, 2H, phenyl-H), 6.94–6.86 (m,
2H, phenyl-H), 5.00 (s, 2H, CH2), 3.68 (s,
3H, OCH3), 3.56 (s, 2H, CH2)
CH3, 4, O, H, C16
H
15BrO3 (335.20)
2.78 mmol (2.0/1.0/4.0)
recrystallization from ‘B’ (58%)
colourless crystals mp 66–68 ◦C
3f
CH3, 4, O, F, C16H14BrFO3 (353.19)
1.75 mmol (2.0/1.0/2.0)
1740, 352/354
1735, 365/367
(CDCl3) 7.42–7.18 (m, 5H, phenyl-H),
6.95–6.88 (m, 2H, phenyl-H), 5.06 (s, 2H,
CH2), 3.69 (s, 3H, OCH3), 3.57 (s, 2H, CH2)
(CDCl3) 7.30–7.23 (m, 3H, phenyl-H), 7.11
(t, J = 7.7 Hz, 1H, phenyl-H), 6.65 (d,
J = 7.8 Hz, 1H phenyl-H), 6.55–6.48 (m,
2H, phenyl-H), 4.35 (d, J = 5.6 Hz, 2H,
NCH2), 4.13 (t, J = 7.1 Hz, 2H, OCH2), 4.06
(br s, 1H, NH), 3.51 (s, 2H, CH2), 1.23 (t,
J = 7.1 Hz, 3H, CH3)
recrystallization from ‘B’ (32%)
colourless crystals mp 38–39 ◦C
2.0 mmol (1.1/1.0/2.2) cc with ‘C’
(59%) yellowish oil
4a
C2H5, 3, NH, F, C17H17BrFNO2
(366.24)
4b
C2H5, 4, NH, F, C17H17BrFNO2
(366.24)
1.4 mmol (2.0/1.0/4.0) cc with ‘C’
(83%) yellow oil
1735, 365/367
(CDCl3) 7.24–7.16 (m, 3H, phenyl-H),
7.10–7.03 (m, 2H, phenyl-H), 6.57–6.50
(m, 2H, phenyl-H), 4.30 (s, 2H, NCH2),
4.16–4.06 (m, 3H, OCH2, NH), 3.47 (s, 2H,
CH2), 1.22 (t, J = 7.1 Hz, 3H, CH3)
a
Equivalents: nucleophile: Rꢀ-Br: base, cc = column chromatography eluents and solvents: ‘A’ = dichloromethane + light petroleum (1 + 1),
‘B’ = diisopropyl ether + light petroleum, ‘C’ = dichloromethane.
0.38 M ammonium sulfate, 0.11 mM NADPH, and 4.7 mM d,l-
glyceraldehyde as substrate in a final volume of 1.5 ml. All
inhibitors were dissolved in DMSO. The final concentration
of DMSO in the reaction mixture was 1%. To correct for the
nonenzymatic oxidation of NADPH, the rate of NADPH oxida-
tion in the presence of all the components except the substrate
was subtracted from each experimental rate. Each dose-effect
curve was generated using at least three concentrations of
inhibitor causing an inhibition between 20 and 80%. Each con-
centration was tested in duplicate and IC50 values as well as
the 95% confidence limits (95% CL) were obtained by using
CalcuSyn software for dose effect analysis (Chou and Hayball,
1996).
3.
Results and discussion
The target compounds were prepared as depicted in Scheme 1.
4-Bromobenzylation or 4-bromo-2-fluorobenzylation of the
appropriate OH- or NH-nucleophile (i.e. hydroxyphenylac-
etates (1) or aminophenylacetates (2), respectively) in the
presence of a base resulted in compounds 3a–f and 4a–b,

european journal of pharmaceutical sciences 2 7 ( 2 0 0 6 ) 188–193
191
Table 2 – Data of compounds of type 5 and 6
No.
Position, X, Rꢀ, formula (MW)
2, O, H, C15H13BrO3 (321.18)
Batch size (yield) purification
properties
IR (cm−1), MS
(CI)
1H NMR
5a
1.0 mmol (91%) recrystallization
from DIPE colourless crystals
mp 117–119 ◦C
1710, 321/323
(CDCl3) 7.45 (‘d’, J = 8.0 Hz, 2H, phenyl-H),
7.31–7.21 (m, 4H, phenyl-H), 7.00–6.87 (m,
2H, phenyl-H), 5.01 (s, 2H, CH2), 3.70 (s, 2H,
CH2)
5b
5c
2, O, F, C15H12BrFO3 (339.17)
3, O, H, C15H13BrO3 (321.18)
1.0 mmol (90%) recrystallization
from DIPE colourless crystals
mp 129–131 ◦C
1.0 mmol (93%) recrystallization
from DIPE colourless crystals
mp 132–134 ◦C
1701, 339/341
1697, 321/323
(CDCl3) 7.38–7.21 (m, 5H, phenyl-H),
7.01–6.90 (m, 2H, phenyl-H), 5.07 (s, 2H,
CH2), 3.69 (s, 2H, CH2)
(CDCl3) 7.51 (d, J = 8.4 Hz, 2H, phenyl-H),
7.32–7.21 (m, 3H, phenyl-H), 6.91–6.85 (m,
3H, phenyl-H), 5.00 (s, 2H, CH2), 3.62 (s, 2H,
CH2)
5d
5e
3, O, F, C15H12BrFO3 (339.17)
4, O, H, C15H13BrO3 (321.18)
0.8 mmol (76%) recrystallization
from DIPE + EA colourless
crystals mp 142–146 ◦C
1.0 mmol (95%) recrystallization
from DIPE + EA colourless
crystals mp 159–161 ◦C
1698, 339/341
1702, 321/323
(CDCl3) 7.43–7.22 (m, 4H, phenyl-H),
6.92–6.86 (m, 3H, phenyl-H), 5.07 (s, 2H,
CH2), 3.63 (s, 2H, CH2)
(CDCl3) 7.51 (d, J = 8.4 Hz, 2H, phenyl-H),
7.29 (d, J = 8.4 Hz, 2H, phenyl-H), 7.20 (d,
J = 8.8 Hz, 2H, phenyl-H), 6.91 (d, J = 8.8 Hz,
2H, phenyl-H), 5.00 (s, 2H, CH2), 3.59 (s, 2H,
CH2)
5f
4, O, F, C15H12BrFO3 (339.17)
0.7 mmol (79%) recrystallization
from DIPE colourless crystals
mp 123–125 ◦C
1.1 mmol (48%) crystallization
from lp beige crystals mp
65–70 ◦C
1695, 339/341
1698, 338/340
(CDCl3) 7.42–7.19 (m, 5H, phenyl-H),
6.96–6.89 (m, 2H, phenyl-H), 5.06 (s, 2H,
CH2), 3.59 (s, 2H, CH2)
(CDCl3) 7.23–7.20 (m 2H, phenyl-H), 7.10 (t,
J = 7.7 Hz, 1H, phenyl-H), 6.63 (d, J = 7.4 Hz,
1H, phenyl-H), 6.54–6.47 (m, 2H, phenyl-H),
4.32 (‘s’, 2H, NCH2), 3.76 (br s, 1H, NH), 3.52
(s, 2H, CH2)
6a
3, NH, F, C15H13BrFNO2
(338.18)
6b
4, NH, F, C15H13BrFNO2
(338.18)
1.1 mmol (63%) recrystallization
from DIPE + EA colourless
crystals mp 158–168 ◦C
1687, 338/340
(DMSO-d6) 11.98 (br s, 1H, COOH), 7.45–7.25
(m, 3H, phenyl-H), 6.92 (d, J = 8.4 Hz, 2H
phenyl-H), 6.48 (d, J = 8.4 Hz, 2H, phenyl-H),
6.08 (‘t’, 1H, NH), 4.24 (d, J = 5.4 Hz, 2H,
NCH2), 3.28 (s, 2H, CH2)
DIPE = diisopropyl ether, EA = ethyl acetate, lp = light petroleum.
Table 3 – Data of compounds 7a and 7b
No.
Position, formula (MW)
Batch size (yield), mp
IR (cm−1), MS (CI)
1693, 1705 434/436
1H NMR
7a
3, C17H12BrF4NO3 × 0.1 light
0.41 mmol (76%), mp
106–110 ◦C
(DMSO-d6) 7.47 (dd, J = 1.9 Hz, J = 9.9 Hz,
1H, phenyl-H), 7.37–7.05 (m, 6H,
phenyl-H), 4.94 (s, 2H, NCH2), 3.54 (s,
2H, CH2)
petroleum (441.41)
7b
4, C17
H
12BrF4NO3 (434.19)
0.62 mmol (65%), mp
91–93 ◦C
1687, 1710 434/436
(DMSO-d6) 7.49 (dd, J = 1.7 Hz, J = 9.7 Hz,
1H, phenyl-H), 7.39–7.15 (m, 6H,
phenyl-H), 4.94 (s, 2H, NCH2), 3.58 (s,
2H, CH2)

192
european journal of pharmaceutical sciences 2 7 ( 2 0 0 6 ) 188–193
Scheme 1
which were converted into the corresponding carboxylic acids
5a–f and 6a–b by alkaline hydrolysis. The trifluoroacetylated
derivatives 7a and 7b became accessible by treatment of the
anilines 6a and 6b with trifluoroacetic acid anhydride. This
modification was of interest in order to study whether the
basic function is critical for enzyme inhibition. The trifluo-
roacetyl substructure was chosen due to its strong electron
withdrawing effect.
Table 4 – Aldose reductase inhibition data
Compound Position
X
Rꢀ Inhibition at
IC50 (␮M)a
50 ␮M (%)
Inhibitory activities of the substituted phenylacetic acids
5a–f, 6a–b, and 7a–b were evaluated in a spectrometric assay
with d,l-glyceraldehyde as the substrate and NADPH as the
cofactor.
5a
5b
5c
5d
5e
5f
6a
6b
7a
7b
2
2
3
3
4
4
3
4
3
4
O
O
O
O
O
O
H
F
H
F
H
F
F
F
F
F
31
47
42
71
44
57
24
22
25
35
53.0 (40.6–69.3)
62.2 (51.1–75.8)
20.9 (18.0–24.3)
58.7 (54.2–63.6)
40.2 (38.3–42.1)
According to the in vitro results obtained (see Table 4), the
phenylacetic acids show satisfying inhibitory activity, hence,
the following conclusions can be drawn: derivatives bearing
the substituted benzyloxy residue either in position 3 (5c,
5d) or 4 (5e, 5f) are favourable to inhibition of the enzyme
compared to the two-substituted isomers (5a, 5b). Interest-
ingly, the data reveal that formal introduction of a fluoro atom
leads not only to increased bioactivity (two- to three-fold) but
also to a diversity considering the effect of the substitution
position (3 versus 4). Thus, out of this series the 3-(4-bromo-
2-fluorobenzyloxy)phenylacetic acid 5d turned out to be the
most potent inhibitor (IC50 = 20.9 ␮M). The corresponding ben-
zoic acid analogue, however, was recently found to exhibit
nearly no activity (3% inhibition at 100 ␮M) (Rakowitz et al.,
2005b) showing that a methylene spacer between the aromatic
core and the acidic function is a critical requirement for aldose
reductase inhibition.
NH
NH
NCOCF3
NCOCF3
a
IC50 values (95% confidence limits).
replacement of O by NH (i.e. 6a and 6b) resulted in a marked
decrease of enzyme inhibition. This effect could be observed
not only for isosters bearing an amino spacer but also for their
corresponding acylated derivatives 7a and 7b.
4.
Conclusions
Therefore, 5d together with the four-substituted congener
served as a basis for additional studies. Initially, we focussed
our interest on the spacer X between the benzene ring and
the substituted benzyl subunit. Here we found that formal
In summary, we have reported on the synthesis and biologi-
cal evaluation of substituted benzyl(oxy/amino)phenylacetic
acids (5a–f, 6a–b, 7a–b), which represent novel aldose
reductase inhibitors. The results of the biological evalua-

european journal of pharmaceutical sciences 2 7 ( 2 0 0 6 ) 188–193
193
complexed with the potent inhibitor zenarestat. Acta Cryst.
D 58, 622–626.
tion allowed us to get insight into initial structural fea-
tures critical for aldose reductase inhibition in this series.
Thus, based on these findings further modifications are
envisaged.
Miyamoto, S., 2002. Recent advances in aldose reductase
inhibitors: potential agents for the treatment of diabetic
complications. Exp. Opin. Ther. Patents 12, 621–631.
Modrakowski, C., Flores, S.C., Beinhoff, M., Schlu¨ ter, A.D., 2001.
Synthesis of pyrene containing building blocks for
dendrimer synthesis. Synthesis, 2143–2155.
Acknowledgement
Podjarny, A., Cachau, R.E., Schneider, T., Van Zandt, M.,
Joachimiak, A., 2004. Subatomic and atomic crystallographic
studies of aldose reductase: implications for inhibitor
binding. Cell. Mol. Life Sci. 61, 763–773.
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Timmermans, P.B.M.W.M., 1995. Balanced AT1/AT2 receptor
antagonists 4. XR510 and related
The authors wish to acknowledge Schlachthof Salzburg-
Bergheim (Austria) (KR Ing. Sebastian Grießner and Mag. Erika
Sakoparnig) for providing calf lenses.
r e f e r e n c e s
5-(3-amidopropanoyl)-imidazoles possessing equal affinity
for the AT1 and AT2 receptors. J. Med. Chem. 38, 2938–2945.
Rakowitz, D., Hennig, B., Nagano, M., Steger, S., Costantino, L.,
Matuszczak, B., 2005a. Synthesis of novel benzoic acid
derivatives with benzothiazolyl subunit and evaluation as
aldose reductase inhibitors. Arch. Pharm. Chem. Life Sci.
338, 411–418.
Rakowitz, D., Muigg, P., Schro¨der, N., Matuszczak, B., 2005b. On
the synthesis of bioisosters of O-benzothiazolyloxybenzoic
acids and evaluation as aldose reductase inhibitors. Arch.
Pharm. Chem. Life Sci. 338, 419–426.
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