Synthesis and biological evaluation of a new set of pyrazolo[1,5-c] quinazolines as glycine/N-methyl-D-aspartic acid receptor antagonists

Article abstract of DOI:10.1248/cpb.57.826

Previous studies have shown that 8-chloro-5,6-dihydro-5-oxo-pyrazolo[1,5-c] quinazoline-2-carboxylates (PQZ series) represent a family of glycine/N-methyl-D-aspartic acid (NMDA) and/or (R,S)-2-amino-3-(3-hydroxy-5- methylisoxazol-4-yl)propionic acid (AMPA

Full text of DOI:10.1248/cpb.57.826

826
Chem. Pharm. Bull. 57(8) 826—829 (2009)
Vol. 57, No. 8
Synthesis and Biological Evaluation of a New Set of Pyrazolo[1,5-
c]quinazolines as Glycine/N-Methyl-D-aspartic Acid Receptor Antagonists
Flavia VARANO,*,a Daniela CATARZI,a Vittoria COLOTTA,a Daniela POLI,a Guido FILACCHIONI,a
b
Alessandro GALLI,b and Chiara COSTAGLI
a Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente
Attivi, Università degli Studi di Firenze; Polo Scientifico e Tecnologico, Via U. Schiff, 6, 50019 Sesto Fiorentino (Firenze),
Italy: and b Dipartimento di Farmacologia Preclinica e Clinica, Università degli Studi di Firenze; Viale G. Pieraccini, 6,
50134 Firenze, Italy. Received March 20, 2009; accepted May 25, 2009; published online May 26, 2009
Previous studies have shown that 8-chloro-5,6-dihydro-5-oxo-pyrazolo[1,5-c]quinazoline-2-carboxylates
(PQZ series) represent a family of glycine/N-methyl-D-aspartic acid (NMDA) and/or (R,S)-2-amino-3-(3-hydroxy-
5-methylisoxazol-4-yl)propionic acid (AMPA) and/or kainic acid (KA) receptor antagonists. Moreover, some
groups have been identified that introduced in suitable positions of the PQZ 2-carboxylate framework shift affin-
ity and selectivity toward glycine/NMDA receptor. These substituents are a carboxylate function at position-1
and/or a chlorine atom at position-9. In this paper we report a study on some new 5,6-dihydro-5-oxo-pyra-
zolo[1,5-c]quinazoline-1-carboxylates bearing at position-2 a lipophilic amide group or lacking substituent at
this same position. All the newly synthesised compounds were evaluated for their binding at glycine/NMDA,
AMPA and KA receptors. These studies led to the identification of some new PQZ derivatives endowed with good
glycine/NMDA receptor affinity and selectivity and to better definition of the structure–activity relationship
(SAR) of this class of compounds.
Key words ionotropic glutamate receptor; glycine and N-methyl-D-aspartic acid receptor; pyrazoloquinazoline; N-methyl-D-
aspartic acid
The amino acid neurotransmitter L-glutamate (Glu) plays a compounds acting as glycine/NMDA and/or AMPA and/
pivotal role in the excitatory pathways of the mammalian or KA receptor antagonists.16—29) One of these classes is
central nervous system where it is involved in the physiologi- represented by the 8-chloro-5,6-dihydro-5-oxo-pyrazolo[1,5-
cal regulation of processes such as neurotransmission, synap- c]quinazoline-2-carboxylates (PQZ series) (Fig. 1) bearing
tic plasticity, learning and memory.1—3)
various substituents on the fused benzo ring and at position-1
Glu mediates its effects via activation of metabotropic (compounds A—D).21,25,28) These studies have provided evi-
(mGluRs) and ionotropic (iGluRs) receptors, the latter con- dence of the structural requirements which are important to
sisting of two major subclasses: N-methyl-D-aspartic acid obtain iGluR receptor antagonists: i) a NH proton donor that
(NMDA) and non-NMDA receptors (kainic acid (KA) and binds to a proton acceptor of the receptor site; ii) the 3 nitro-
(R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propi- gen atom and the oxygen atom of the 5-carbonyl group that
onic acid (AMPA) receptors).4)
are d-negatively charged heteroatoms able to form a coulom-
It is well known that excessive release of Glu from presy- bic interaction with a positive site of the receptor; iii) a car-
naptic terminals and the subsequent overstimulation of post- boxylate function at position-2 able to engage a strong hy-
synaptic GluRs cause excitotoxic mechanisms that play a drogen-bond interaction with a cationic proton donor site of
critical role in the pathophysiology of several acute and the receptor; and iv) an electron-withdrawing substituent at
chronic neurological pathologies such as cerebral ischemia, position-8 on the fused benzo moiety. These studies have
epilepsy, Alzheimer’s and Parkinson’s diseases, and amy- also shown that introduction of a carboxylate moiety at posi-
otrophic lateral sclerosis.2,5)
tion-1 or of a chlorine atom at position-9 of the parent com-
Antagonists of NMDA or non-NMDA receptors are there- pound A shifts affinity and selectivity toward glycine/NMDA
fore of great therapeutic interest for the treatment of brain receptor (compounds B and C, respectively) (Fig. 1). Finally
diseases which are pathophysiologically linked to excessive it has been demonstrated that the contemporary presence of
excitatory amino acid receptor activation.2)
these substituents (compound D) is well tolerated by the
Targeting the NMDA receptor is a promising approach to glycine/NMDA receptor (Fig. 1).
anti-excitotoxic therapy, however competitive NMDA recep-
To gain more information from SAR studies and in the at-
tor antagonists cause undesirable side effects such as halluci- tempt to optimize glycine/NMDA receptor affinity and selec-
nations, ataxia, and motor incoordination that prevent their tivity of PQZ derivatives, a new set of related analogues 1—
clinical use. Aiming at the glycine coagonist site of the
NMDA receptor complex may bypass these shortcomings. In
addition, glycine/NMDA receptor antagonists have other po-
tential therapeutic applications, such as for the treatment of
traumatic brain injury, chronic pain, drug and alcohol abuse
and tolerance.6—15)
Over the past decade, our laboratory has been notably in-
volved in the elucidation of the structure–activity relation-
Fig. 1. Previously Reported PQZ Derivatives
© 2009 Pharmaceutical Society of Japan
ship (SAR) of different chemical classes of heterocyclic
∗ To whom correspondence should be addressed. e-mail: flavia.varano@unifi.it

August 2009
827
10 was developed (Fig. 2). Compounds 1—10, while main- Results and Discussion
taining a carboxylate function at position-1, possess an
The pyrazoloquinazolines 1—10, together with DCKA
amide moiety at position-2 (compounds 1—6) or lack a sub- (5,7-dichlorokynurenic acid) and NBQX (2,3-dihydroxy-6-
stituent at this same position (compounds 7—10) (Fig. 2). It nitro-7-sulphamoylbenzo[f]-quinoxaline) as standard com-
has to be noted that 1—6 bear a lipophilic amide side chain pounds, were tested for their ability to displace tritiated
similarly to a number of bicyclic or tricyclic heteroaromatic glycine from its specific binding in rat cortical membranes.
derivatives reported as potent and selective glycine/NMDA AMPA and high-affinity KA binding assays were also per-
receptor antagonists.15) Moreover, the glycine/NMDA recep- formed on rat cortical membranes. The binding results are
tor pharmacophore model reported in the literature15,30) shown in Table 1 together with those of the previously re-
shows a hydrophobic pocket that well accommodates bulky ported PQZ derivatives B25) C21) and D25) included as refer-
groups in a region of the receptor site corresponding to posi- ence compounds.
tion-2 of the PQZ scaffold.
The binding results indicate that synthesis of compounds
All the newly synthesised compounds were biologically 1—10 produced some new glycine/NMDA receptor antago-
evaluated for their binding at the glycine/NMDA receptor. nists. Indeed, the 2-amido 4—6 and the 2-unsubstituted de-
AMPA and KA high-affinity binding assays were also per- rivatives 8 and 10 are endowed with glycine/NMDA receptor
formed to assess the selectivity of the reported compounds
toward the glycine/NMDA receptor.
Chemistry The target derivatives 1—10 were prepared
as depicted in Chart 1. The starting 1-(ethoxycarbonyl)-5,6-
dihydro-5-oxo-pyrazolo[1,5-c]quinazoline-2-carboxylic acids
11, 12, and the ethyl 5,6-dihydro-5-oxo-pyrazolo[1,5-
c]quinazoline-1-carboxylates 7 and 8 were prepared as previ-
ously reported.25) Reaction of 11 and 12 with suitable amines
gave the 2-carboxyamides 1—3. Finally, by treatment of es-
ters 1—3, 7, 8 in alkaline medium the corresponding acids
4—6, 9, 10 were obtained.
Reagents: (a) EDC hydrochloride, HOBt, R2NH2, DMF, room temperature; (b) heat-
ing over the melting points; (c) i) 2 M KOH/EtOH, room temperature, ii) 6 M HCl.
Fig. 2. Currently Reported PQZ Derivatives
Chart 1
Table 1. Binding Affinities at Glycine/NMDA, AMPA and KA Receptors
Ki (mM)a) or I%b)
IC50 (mM)d) or I%b)
Selectivity
Compd.
R9
R1
R2
ratioc)
[3H]glycine
[3H]AMPA
[3H]kainate
Be)
H
Cl
Cl
H
H
Cl
H
H
Cl
H
Cl
H
Cl
—
—
COOH
H
COOH
COOH
COOH
CONHPh
CONHCH2Ph
CONHPh
CONHPh
CONHCH2Ph
CONHPh
H
0.09ꢀ0.01
0.16ꢀ0.04
0.059ꢀ0.01
9.5ꢀ2.0
44ꢀ6.0
1.1ꢀ0.2
2.4ꢀ0.8
0.71ꢀ0.08
42%
18ꢀ0.9
16%
3.4ꢀ0.3
3.8ꢀ0.2
1.8ꢀ0.3
32%
8.3ꢀ2.5
6.4ꢀ0.7
5.8ꢀ0.8
5%
12.2
15
12
ꢁ10
0.4
—
5.9
7.3
15
—
11.8
2.6
21.5
ꢁ1000
ꢂ1000
11.5ꢀ1.4
41ꢀ3.0
19.5ꢀ1.1
19%
Cf)
De)
1
2
3
4
5
6
7
8
9
10
DCKA
NBQX
COOH
COOEt
COOEt
COOEt
COOH
COOH
COOH
COOEt
COOEt
COOH
COOH
—
7%
9%
28%
0.58ꢀ0.08
0.52ꢀ0.05
0.12ꢀ0.01
36%
0.70ꢀ0.15
2.5ꢀ0.4
0.27ꢀ0.05
0.09ꢀ0.02
3%
18.5ꢀ1.2
33ꢀ2
17ꢀ3
4%
91ꢀ11
48%
27.5ꢀ3.4
8%
7.0ꢀ1.1
H
H
H
—
—
—
0.07ꢀ0.06
a) Inhibition constant (Ki) values were meansꢀS.E.M. of three or four separate determinations in triplicate. b) Percentage of inhibition (I%) of specific binding at 100 mM
concentration. c) Glycine/NMDA versus AMPA selectivity ratio. d) Concentrations necessary for 50% inhibition (IC50). The IC50 values were meansꢀS.E.M. of three or four
separate determinations in triplicate. e) Ref. 25. f) Ref. 21.

828
Vol. 57, No. 8
Table 2. Physical Data of the Newly Synthesised Compounds
affinities in the low micromolar range. Affinities of com-
pounds 1—10 for both AMPA and KA receptors are gener-
ally lower than those for the glycine/NMDA one even if they
generally show AMPA receptor binding affinities in the mi-
cromolar range.
Replacement of the 2-carboxylic group of lead compounds
B and D with a lipophylic amide side chain is tolerated by all
three receptor types. Generally, 4—6 bind to the receptor
sites even if with lower affinities with respect to those of B
and D. However, it has to be noted that glycine/NMDA and
AMPA receptor affinities of the 2-phenylcarbamoyl-1-car-
boxylic acid 6 are only about 2-fold lower than those of the
previously reported 1,2-dicarboxylic acid B. As expected 1,
2, 4—6 show higher glycine/NMDA receptor binding affini-
ties than those at AMPA and KA receptors, thus confirming
that the presence of a lipophilic side chain is tolerated espe-
cially by the glycine/NMDA receptor.
Compd.
mp [°C]
Solventa)
Yield [%]
1
2
3
4
5
6
9
10
283—286
ꢁ300
291—294
ꢁ300
ꢁ300
ꢁ300
A
A
A
B
C
A
B
C
85
90
95
75
70
70
80
85
ꢁ300
ꢁ300
a) Recrystallization solvents: Aꢄglacial acetic acid; Bꢄdimethylformamide/water;
Cꢄdimethylformamide.
by addition of D2O. The physical data of new compounds are shown in Table
2.
8-Chloro-1-(ethoxycarbonyl)-5-oxo-5,6-dihydro-pyrazolo[1,5-c]quina-
zoline-2-carboxylic Acid (11), and 8,9-Dichloro-1-(ethoxycarbonyl)-5-
oxo-5,6-dihydro-pyrazolo[1,5-c]quinazoline-2-carboxylic Acid (12) The
title compounds were prepared as previously reported.25)
General Procedure for the Preparation of 2-Carboxyamides 1—3 N-
3-(Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC hy-
drochloride) (1.64 mmol), 1-hydroxybenzotriazole (HOBt) (1.64 mmol) and
the suitable amine (1.64 mmol) were successively added to a solution of 11,
12 (1.49 mmol) in anhydrous N,N-dimethylformamide (DMF) (5 ml). The
mixture was stirred at room temperature for 12 h and then dilution with
Particularly interesting are the binding data, in general in
the micromolar range, of the 1-carboxy-2-unsubstituted de-
rivatives 8—10. Compound 10 is worthy of note: while lack-
ing 2-carboxylic group of D it is able in any case to bind at
all three receptor types. This was unexpected because up to
now the presence at position-2 of a substituent able to engage
either a hydrogen-bond or a lipophylic interaction with the 0.1 M HCl (15 ml) afforded a precipitate which was collected by filtration
and washed with water. Compounds 1—3 displayed the following spectral
and analytical data:
receptor sites was thought to be an important structural re-
quirement for the anchoring of PQZ derivatives at the three
Ethyl 8-Chloro-5-oxo-2-(phenylcarbamoyl)-5,6-dihydro-pyrazolo[1,5-c]
receptor types.15,30) It has to be noted that binding affinities at
1
quinazoline-1-carboxylate 1: H-NMR d: 1.13 (3H, t, Jꢄ6.9 Hz), 4.27 (2H,
glycine/NMDA, AMPA and KA receptors of the 2-unsubsti-
tuted-1-carboxylic acid 10 are comparable to those of its cor-
responding 1-unsubstituted-2-carboxylic acid C.21) This find-
ing represents a novelty and indicates that the position of the
carboxylate group in the upper region of the PQZ scaffold
does not affect anchoring at the receptor sites.
q, Jꢄ6.9 Hz), 7.15 (1H, m), 7.40 (4H, m), 7.75 (2H, d, Jꢄ7.6 Hz), 8.83 (1H,
d, Jꢄ8.8 Hz), 10.79 (1H, s), 12.48 (1H, br s) Anal. Calcd for C20H15ClN4O4:
C, 58.47; H, 3.69; N, 13.64. Found: C, 58.23; H, 3.50; N, 13.79.
Ethyl 2-(Benzylcarbamoyl)-8-chloro-5-oxo-5,6-dihydropyrazolo[1,5-c]
1
quinazoline-1-carboxylate 2: H-NMR d: 1.18 (3H, t, Jꢄ6.9 Hz), 4.26 (2H,
q, Jꢄ6.9 Hz), 4.45 (2H, d, Jꢄ6.2 Hz), 7.33 (7H, m), 8.52 (1H, d, Jꢄ9.1 Hz),
9.30 (1H, m), 12.38 (1H, s) Anal. Calcd for C21H17ClN4O4: C, 59.36; H,
4.04; N, 13.19. Found: C, 59.53; H, 4.15; N, 13.23.
As previously reported,21,25,28) the presence of a chlorine
atom at position-9 of the PQZ framework is an important
structural requirement for enhancing glycine/NMDA recep-
tor affinity and selectivity. In fact, the 9-chloro derivatives 6,
8, and 10 possess glycine/NMDA receptor affinities and se-
lectivities which are higher than those of their corresponding
9-unsubstituted derivatives 4, 7, and 9.
Ethyl 8,9-Dichloro-5-oxo-2-(phenylcarbamoyl)-5,6-dihydro-pyrazolo[1,5-
c]quinazoline-1-carboxylate 3: 1H-NMR d: 1.12 (3H, t, Jꢄ7.0 Hz), 4.28
(2H, q, Jꢄ7.0 Hz), 7.12 (1H, t, Jꢄ7.7 Hz), 7.37 (2H, t, Jꢄ7.7 Hz), 7.58 (1H,
s), 7.74 (2H, d, Jꢄ7.7 Hz), 9.21 (1H, s), 10.81 (1H, s), 12.60 (1H, br s) IR
cmꢃ1: 3490, 3284, 1755, 1707, 1659. Anal. Calcd for C20H14Cl2N4O4: C,
53.94; H, 3.18; N, 12.59. Found: C, 53.79; H, 3.19; N, 12.50.
Ethyl 8-Chloro-5-oxo-5,6-dihydro-pyrazolo[1,5-c]quinazoline-1-car-
boxylate (7) and Ethyl 8,9-dichloro-5-oxo-5,6-dihydro-pyrazolo[1,5-
c]quinazoline-1-carboxylate (8) The title compounds were prepared by
heating 11, 12 in an oil bath over their melting points, according to the pro-
Finally, affinities of the 1-carboxylic acids 4—6, 9—10 are
generally higher than those of their corresponding esters 1—
3, 7—8, demonstrating that the presence of a free carboxy- cedure reported in ref. 25.
General Procedure for the Preparation of the 1-Carboxylic Acids 4—
late group at position-1 is important for anchoring at all three
receptor types.
6, 9, 10 An aqueous solution of KOH (2 M, 3 ml) was added to a suspen-
sion of the ethyl 1-carboxylate esters 1—3, 7, 8 (0.6 mmol) in EtOH (15 ml).
The mixture was stirred at room temperature until the disappearance of the
starting material (TLC monitoring, eluting system CHCl3/MeOH 9 : 1) and
then diluted with water (30 ml). The clear cold (5 °C) solution upon acidifi-
cation with 6 M HCl afforded a solid which was collected by filtration and
washed with water. Compounds 4—6, 9, 10 displayed the following spectral
and analytical data:
In conclusion, the synthesis of the herein reported 1-car-
boxy PQZ derivatives produced new glycine/NMDA receptor
antagonists endowed with good affinity and selectivity, and
allowed us to further investigate the SAR of tricyclic het-
eroaromatic systems as iGluR receptor antagonists.
8-Chloro-5-oxo-2-(phenylcarbamoyl)-5,6-dihydro-pyrazolo[1,5-c]quin-
1
Experimental
azoline-1-carboxylic Acid 4: H-NMR d: 7.10 (1H, m), 7.37 (4H, m), 7.71
Chemistry Silica gel plates (Merk F254) and silica gel 60 (Merck; 70—
(2H, d, Jꢄ8.0 Hz), 8.93 (1H, d, Jꢄ9.1 Hz) 10.76 (1H, s), 12.43 (1H, s),
230 mesh) were used for analytical and column chromatography, respec- 13.52 (1H, br s) Anal. Calcd for C18H11ClN4O4: C, 56.48; H, 2.90; N, 14.64.
tively. All melting points were determined on a Gallenkamp melting point Found: C, 56.67; H, 2.99; N, 14.70.
apparatus. Microanalyses were performed with a Perkin-Elmer 260 elemen-
2-(Benzylcarbamoyl)-8-chloro-5-oxo-5,6-dihydro-pyrazolo[1,5-c]quina-
1
tal analyser for C, H, N. The IR spectra were recorded with a Perkin-Elmer zoline-1-carboxylic Acid 5: H-NMR d: 4.48 (2H, d, Jꢄ6.2 Hz), 7.34 (7H,
1
1420 spectrometer in Nujol mulls and are expressed in cmꢃ1. The H-NMR m), 8.82 (1H, d, Jꢄ8.4 Hz), 9.42 (1H, t, Jꢄ6.2 Hz), 12.37 (1H, s), 13.87
spectra were obtained with a Varian Gemini 200 instrument at 200 MHz. (1H, br s) Anal. Calcd for C19H13ClN4O4: C, 57.51; H, 3.31; N, 14.12.
The chemical shifts are reported in d (ppm) and are relative to the central Found: C, 57.44; H, 3.42; N, 14.18.
peak of the solvent, which is always DMSO-d6. The following abbreviations
are used: s=singlet, dꢄdoublet, ddꢄdouble doublet, tꢄtriplet, qꢄquartet,
mꢄmultiplet, and brꢄbroad. All the exchangeable protons were confirmed 7.36 (2H, m), 7.56 (1H, s), 7.73 (2H, d, Jꢄ7.2 Hz), 9.32 (1H, s), 10.81 (1H,
8,9-Dichloro-5-oxo-2-(phenylcarbamoyl)-5,6-dihydro-pyrazolo[1,5-
c]quinazoline-1-carboxylic acid 6: 1H-NMR d: 7.12 (1H, t, Jꢄ7.0 Hz),

August 2009
829
s), 12.54 (1H, s) IR cmꢃ1: 3664, 3510, 1767, 1696. Anal. Calcd for
C18H10Cl2N4O4: C, 51.81; H, 2.42; N, 13.43. Found: C, 52.01; H, 2.44; N,
13.36.
(2006).
16) Varano F., Catarzi D., Colotta V., Cecchi L., Filacchioni G., Galli A.,
Costagli C., Arch. Pharm. Pharm. Med. Chem., 332, 201—207 (1999).
17) Catarzi D., Colotta V., Varano F., Cecchi L., Filacchioni G., Galli A.,
Costagli C., J. Med. Chem., 42, 2478—2484 (1999).
18) Catarzi D., Colotta V., Varano F., Cecchi L., Filacchioni G., Galli A.,
Costagli C.,Carlà V., J. Med. Chem., 43, 3824—3826 (2000).
19) Varano F., Catarzi D., Colotta V., Cecchi L., Filacchioni G., Galli A.,
Costagli C., Eur. J. Med. Chem., 36, 203—209 (2001).
8-Chloro-5-oxo-5,6-dihydro-pyrazolo[1,5-c]quinazoline-1-carboxylic
1
Acid 9: H-NMR d: 7.39 (2H, m), 8.40 (1H, s), 9.38 (1H, d, Jꢄ8.7 Hz),
12.30 (1H, br s). Anal. Calcd for C11H6ClN3O3: C, 50.11; H, 2.30; N, 15.94.
Found: C, 49.99; H, 2.21; N, 16.01.
8,9-Dichloro-5-oxo-5,6-dihydro-pyrazolo[1,5-c]quinazoline-1-carboxylic
Acid 10: 1H-NMR d: 7.48 (1H, s), 8.39 (1H, s), 9.60 (1H, s), 12.40 (1H, s),
13.35 (1H, br s) IR cmꢃ1: 3170, 1734, 1712. Anal. Calcd for C11H5Cl2N3O3:
C, 44.32; H, 1.69; N, 14.10. Found: C, 44.21; H, 1.58; N, 14.03.
20) Catarzi D., Colotta V., Varano F., Filacchioni G., Galli A., Costagli
C.,Carlà V., J. Med. Chem., 44, 3157—3165 (2001).
21) Varano F., Catarzi D., Colotta V., Filacchioni G., Galli A., Costagli C.,
Carlà V., J. Med. Chem., 45, 1035—1044 (2002).
Pharmacology. Binding Assays Rat cortical synaptic membrane
preparation, [3H]glycine and [3H]AMPA binding experiments were per-
formed following the procedure described in refs. 31 and 32, respectively.
High-affinity [3H]kainate binding assays were performed on rat cortical
membranes according to previously reported methods.22)
Sample Preparation and Result Calculation A stock of 1 mM solution
of the tested compound was prepared in 50% DMSO. Subsequent dilutions
were accomplished in buffer. The IC50 values were calculated from three to
four displacement curves based on four to six scalar concentrations of the
tested compound in triplicate using the ALLFIT computer program33) and, in
the case of tritiated glycine and AMPA binding, converted to Ki values by
application of the Cheng–Prusoff equation.34) In our experimental conditions
the dissociation constants (KD) for [3H]glycine (10 nM) and [3H]-DL-AMPA
(8 nM) were 75ꢀ6 and 28ꢀ3 nM, respectively.
22) Catarzi D., Colotta V., Varano F., Calabri F. R., Filacchioni G., Galli
A., Costagli C., Carlà V., J. Med. Chem., 47, 262—272 (2004).
23) Colotta V., Catarzi D., Varano F., Calabri F. R., Filacchioni G., Costagli
C., Galli A., Bioorg. Med. Chem. Lett., 14, 2345—2349 (2004).
24) Calabri F. R., Colotta V., Catarzi D., Varano F., Lenzi O., Filacchioni
G., Costagli C., Galli A., Eur J. Med. Chem., 40, 897—907 (2005).
25) Varano F., Catarzi D., Colotta V., Calabri F. R., Lenzi O., Filacchioni
G., Galli A., Costagli C., Deflorian F., Moro S., Biorg. Med. Chem.,
13, 5536—5549 (2005).
26) Colotta V., Catarzi D., Varano F., Lenzi O., Filacchioni G., Costagli C.,
Galli A., Ghelardini C., Galeotti N., Gratteri P., Sgrignani J., Deflorian
F., Moro S., J. Med. Chem., 49, 6015—6026 (2006).
27) Bacilieri M., Varano F. , Deflorian F., Marini M., Catarzi D., Colotta V.,
Filacchioni G., Galli A., Costagli C., Kaseda C., Moro S., J. Chem. Inf.
Model, 47, 1913—1922, (2007).
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