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Expert Opinion on Drug Discovery

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Recent advances in the design and synthesis of

prazosin derivatives
a a a a
Anna Minarini , Maria Laura Bolognesi , Vincenzo Tumiatti & Carlo Melchiorre
a
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6,
40126 Bologna, Italy.
Published online: 31 Mar 2015.

To cite this article: Anna Minarini, Maria Laura Bolognesi, Vincenzo Tumiatti & Carlo Melchiorre (2006) Recent advances
in the design and synthesis of prazosin derivatives, Expert Opinion on Drug Discovery, 1:5, 395-407

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1. Introduction
2. Design of prazosin derivatives
3. Synthesis of prazosin derivatives
4. Conclusion
5. Expert opinion
Downloaded by [Emory University] at 15:52 09 August 2015
10.1517/17460441.1.5.395 © 2006 Informa UK Ltd ISSN 1746-0441
Review
Recent advances in the design and
synthesis of prazosin derivatives
Anna Minarini†, Maria Laura Bolognesi, Vincenzo Tumiatti
& Carlo Melchiorre
†Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy
Due to the large number of therapeutic indications, particularly for antago-
nists, a field of constant interest in medicinal chemistry is the design, synthesis
and pharmacological evaluation of ligands that bind at α1-adrenoreceptors,
which include α1a, α1b and α1d subtypes. This review, which is mainly based on
literature over the past 10 years, focuses on the developments of some of the
most potent, selective and widely used α1-adrenoreceptor antagonists that are
structurally related to prazosin (which is characterised by a quinazoline moi-
ety). Initially introduced in therapy for the management of hypertension, pra-
zosin derivatives have become increasingly common in the treatment of
benign prostatic hyperplasia. During the past few years, new perspectives have
emerged for the use of these derivatives as a novel class of apoptosis-inducing
agents in prostate cancer.
Keywords: α-adrenergic antagonist, cyclazosin, prazosin, quinazoline
Expert Opin. Drug Discov. (2006) 1(5):395-:407
1. Introduction
The α1-adrenoreceptors (α1-ARs) are classified into three well-characterised sub-
types, based on their molecular and pharmacological properties namely, α1a, α1b,
and α1d [1,2]. The effort to design agents selective for each of the three α1-AR sub-
types has been an active area of research due to the wide number of possible thera-
peutic applications. The α1-AR family is of great therapeutic interest because of its
fundamental role in cardiovascular function, particularly in the regulation of blood
pressure [3]. Although initially introduced for the management of hypertension,
α1-AR antagonists have become increasingly common in the treatment of lower uri-
nary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH), as they relax
smooth muscle and thereby relieve urinary retention [4-7].
Some of the most potent, selective and widely used α1-AR antagonists are struc-
turally characterised by a quinazoline ring. Prazosin (1) represents the progenitor of
this class, and was one of the first α1-AR antagonists able to discriminate between
α1- and α2- families that were introduced in therapy as an antihypertensive agent.
Its antihypertensive activity depends on peripheral vasodilation mediated by a
postjunctional α1-AR blockade. However, due to the lack of selectivity of prazosin
among the three α1-AR subtypes, much research effort has been directed towards
the design and synthesis of more selective compounds using the structure of pra-
zosin as a template. Some congeners of prazosin, such as terazosin (2), doxazosin (3)
and alfuzosin (4), which offer a similar antihypertensive effect with a longer duration
of action, have been widely studied for the treatment of BPH [6,8]. The efficacy of
these α1-AR antagonists in BPH is balanced against a small, but significant, inci-
dence of side effects, such as orthostatic hypotension. Due to its preferential
distribution into the prostate gland, compound 4 emerged as a uroselective agent for
the management of BPH associated with a significantly lower incidence of
cardiovascular effects [9] (Figure 1).
395
 Recent advances in the design and synthesis of prazosin derivatives

NH 2
NH 2 N H2
O
N O O
N N
O N N O O
O N N O O N N
N
N N
O O
1 Prazosin 2 Terazosin O 3 Doxazosin O

NH 2 NH 2
O O
N O N H2
R2 O
O N
O N N N O N
H
R1 R2
O
4 Alfuzosin 5
6 R1
NH 2
NH 2 O N H2
N
O O
N N
O N N
O N N N O N N
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CO O CH 2 Ph
N N N O
O CO NHt-Bu
10 O O 11 L-765314 N N
12
O
N H2
O HN N O
N O
N HN
N
O N N
H R N N
N N CO O CH 2 CH 3
O
N
H N N
O H
13 33 FH-71
34 EW -154
O
O
O NH O R2 O
RO
NH O N N NH
Y
O N N O R1O N N Ar
N R3
N

36 37
35
O

NH 2 N H2
O O
O O
O N
N
N N3
N O N N
O N O
X N N
HN R N
Ar I

O O
38 39 52 IAAP

Figure 1. Structure of prazosin (1) and related α-AR antagonists.

The relative importance of the various α1-AR subtypes in selectivity for inhibition of prostatic pressure/tone versus
BPH is still controversial as it has yet to be determined blood pressure [10]. On the other hand, increasing evidence
which subtype-selectivity profile provides the best therapeu- indicates that the α1d-AR subtype predominates in the blad-
tic advantage in terms of targeting the prostate. However, der detrusor muscle, supporting its role in mediating the
high affinity and selectivity for prostatic α1a-ARs, irritative symptoms in BPH. In fact, the
particularly versus the α1b subtype, seem to confer optimal methoxybenzenesulfonamide-based α1-AR antagonist

396 Expert Opin. Drug Discov. (2006) 1(5)


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Figure 2. Complex of prazosin (1) at the ligand binding site.
EL: Extracellular loop; TM: Transmembrane domain.
Reprinted from M Ishiguro, Y Futabayashi, T Ohnuki, M Ahmed,
I Muramatsu, T Nagamoto: Identification of binding site of prazosin, tamsulosin
and KMD-3213 with α-adrenergic receptor subtypes by molecular modeling.
Life Sciences, 71, 2531-2541, Copyright (2002), with permission from Elsevier.
tamsulosin, which has high affinity for α1a-AR and α1d-AR
subtypes over α1b-ARs, shows efficacy in BPH associated
with fewer side effects [7]. This is similar to the nonsubtype
selective compounds 2 and 3. Therefore, in the last decade,
research efforts in this area have been directed towards the
discovery of subtype-selective quinazoline derivatives. The
aim of this review is to provide an update on the current
knowledge of the design and synthesis of α1-antagonists
based on the structure of prazosin.
2. Design of prazosin derivatives
To investigate the role of the different main fragments of pra-
zosin in receptor binding, a wide range of structure–activity
relationship studies were performed on the structure of pra-
zosin. To this end, multiple modifications involved the
piperazine and furan rings, mainly by conserving the
2,4-diamino-6,7-dimethoxyquinazoline moiety.
The role of the 2,4-diamino-6,7-dimethoxyquinazoline
moiety in the receptor recognition process has been
investigated in depth. Initially, it was suggested that this
moiety could act as a conformationally restricted form of
the noradrenaline cation and that a dominant role in the
receptor recognition process was played by the protonated
N-1 of the quinazoline system, which mimicked the amine
function of the neurotransmitter [11]. In particular, a
charged-reinforced H-bond interaction involving the
quinazoline-N-1 function and an anionic site of the
receptor was highlighted [12,13].
Expert Opin. Drug Discov. (2006) 1(5)
Minarini, Bolognesi, Tumiatti & Melchiorre
Later, due to the large availability of α1-AR antagonists,
many groups have attempted to develop a pharmacophore for
α1-AR subtypes, reaching the conclusion that it is not possible
to construct a model that is valid for all the structurally differ-
ent classes of ligands. In particular, the relative positions of the
protonated nitrogen atom and the aromatic systems differ for
quinazoline derivatives, raising the so-called ‘prazosin prob-
lem’. From the obtained results, it is quite likely that the pra-
zosin derivatives (which generally exhibit very high affinity for
all three α1-AR subtypes, but little subtype selectivity) bind to
a site that is different from that of other antagonists, and
common to all α1-ARs [14,15].
More recently, a model of the prazosin α1-AR interaction,
built by the use of the coordinates of rhodopsin, confirmed
the N-1 function on the quinazoline ring to be one of the key
groups involved in receptor binding, together with the two
methoxy moieties, the 4-amino group and the carbonyl func-
tion. The docking studies into all the α1-AR subtypes sug-
gested that the 4-amino group on the quinazoline ring
possibly interacts with the carboxyl group of an aspartate resi-
due in transmembrane (TM)3 and the N-1 atom with the
hydroxyl group of a serine in TM5, through hydrogen bond
formations. Furthermore, the two methoxy groups of quina-
zoline ring may also interact with hydroxyl groups of a threo-
nine in TM3 and of a serine in TM5, whereas the carbonyl
group is presumed to form a hydrogen bond with a serine in
TM6 (Figure 2). The suggested identical interactions for pra-
zosin within all the α1-AR subtypes, accounted for its lack of
selectivity [16].
One of the first attempts to manipulate the structure of
prazosin was the replacement of its furan ring with a 1,4-ben-
zodioxane moiety, which is a well known pharmacaphore for
antihypertensive activity [17]. This modification led to the dis-
covery of compound 3, endowed with a longer duration of
action that allowed a once-daily administration in humans.
To demonstrate the importance of the N-1 atom and the
effect of its protonability, the quinazoline nucleus of prazosin
was replaced by isosteric heteroaromatic systems such as quin-
oline (5) and isoquinoline (6) rings. The comparable biologi-
cal activity in binding assays of compound 5 derivatives with
prazosin demonstrated that, presumably, their nitrogen atoms
play a common role in the α-AR recognition process, as their
basic values allowed protonation at physiological pH. The
poor affinity showed by compound 6 derivatives confirmed
that isosteric relocation of the nitrogen atom within the ring
was unacceptable, and outlined the importance of N-1-proto-
nation in the receptor interaction process [18,19].
On the basis of these results and once the electronic
requirements of the quinazoline moiety were satisfied, most of
the efforts to modulate binding affinities were directed to the
modification of the quinazoline 2-substituent. Thus, the role
of the piperazine ring was initially investigated through its
replacement by an α,ω-alkanediamine chain, revealing that
this moiety may not be essential for α1 blocking activity, and
that the length of the alkane chain and N-methylation of both
397
 Recent advances in the design and synthesis of prazosin derivatives

NH2
O
N

O N N
N
O
O

Prazosin 1 α1A = 8.60

α1B = 8.99
α1D = 8.91

NH2
O
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O N N
N
O
O

7: α1A = 9.04
α1B = 9.84
α1D = 9.19

NH2 NH2
O O
N N

O N N O N N
H
N N
O O
H
O S O
S

(+)-Cyclazosin 8: α1A = 7.73 Cystazosin 9: α1A = 7.53

α1B = 8.85 α1B = 7.49
α1D = 7.27 α1D = 8.54

Figure 3. Design strategy and affinity profile (pA2 values) at α-AR subtypes of compounds 7 – 9 [23].
the amide and the 2-amino function could efficiently tune
affinity and selectivity towards α1- over α2-ARs. In this con-
text, compound 7 with a hexamethylenediamino chain, dis-
played the higher antagonist potency and selectivity (Figure 3)
[20]. Consequently, different structural modifications were
performed on the piperazine ring, all of them leading to com-
pounds supporting the presence of a lipophilic binding area
on the surface of the α1-AR [21]. To better define the size and
the sterochemical requirements of this area, several derivatives
(in which the hexamethylene chain of compound 7 is partially
or totally incorporated into a constrained nucleus) were
designed. The aim of this structural modification was to keep
the quinazoline and furan rings in a position similar to that of
prazosin, forcing the alkane moiety to assume a definite spa-
tial arrangement. The difference in activity between the two
cis/trans diasteroisomers not only supported the presence of
the lipophilic binding area on α1-ARs surface, but, in addi-
tion, demonstrated that the lipophilic pocket is endowed with

398 Expert Opin. Drug Discov. (2006) 1(5)


OCH 3
X NH 2
N ( ) N
H 4 H O
15 X = S
2 R
NH 2
O
N
O N
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NH 2
O
N
O N
Figure 4. Design strategy of derivatives 16 – 27.
a well-defined size and spatial orientation. Among the synthe-
sised compounds (+)-cyclazosin (8) [22], which incorporates a
cis-perhydroquinoxaline nucleus, displayed the most promis-
ing affinity profile, leading to a selective α1b-AR antagonist, as
reviewed in detail [23] (Figure 3).
A steric discrimination is probably responsible for the
α1b-AR selectivity of compound 8, in line with the trend of
affinity found for compound 10 [24] and L-765314 (11) [25],
which also bear bulky substituents and a preferential interac-
tion with the α1b-AR subtype. Furthermore, cystazosin (9),
obtained by replacing the hexanediamino chain of compound
7 with a cystamine moiety, displayed a favourable affinity
profile, leading to a selective α1d-AR antagonist [26].
In 2004, the (4aR,8aS) configuration of compound 8 was
assigned by means of an X-ray crystallographic study of the
(R,R)-(+)-tartrate salts of the chiral precursor (+)- and (-)-2-furyl
(cis-perhydro-1-quinoxalinyl)-methanone [27]. The higher
α1b-AR selectivity of compound 8 relative to the (-)-enantiomer
has to be ascribed to its lower affinity towards the other α1-AR
subtypes, which might be due to a negative influence of the
tetramethylene portion of the perhydroquinoxaline system in the
interaction process with α1a- and α1d-AR subtypes. The α1b-AR
selectivity of compound 8 over α1a- and α1d-AR subtypes has
Expert Opin. Drug Discov. (2006) 1(5)
Minarini, Bolognesi, Tumiatti & Melchiorre
N
O N N
N
14
O
CH 2 NH(CH 2)6 NH(CH 2)2 X
N
N
O 2
16 – 21 X = S, CH 2
CH 2 NH(CH 2)6 NH(CH 2)2 X
N
N
O 2
22 – 27 X = S, CH 2
been confirmed in functional studies that have been performed
on rat and rabbit tissues, making it a useful tool for the pharma-
cological characterisation of the α1b-AR [28].
In the search for new analogues compound 8 may demon-
strate increased affinity and selectivity for α1b-ARs, a
number of racemic compounds, bearing different substitu-
ents as an alternative to the 2-furoyl moiety, were synthe-
sised and pharmacologically evaluated [29]. Binding results
indicated that the majority of the compounds showed a
trend of preferential affinity for α1d- and α1b-ARs, similar to
that of racemic compound 8, although the most potent of
the series, the 4,6-dimethoxy-substituted triazine derivative
compound 12 (Figure 1) presented comparable affinity at
α1a-, α1b- and α1d-ARs, with pKi values of 10.15, 10.22 and
10.40, respectively. Taken together, the binding results indi-
cated that the α1a-AR would express a more specific struc-
tural demand in the N-4-substituent for optimum
interaction, when compared with α1d- and α1b-ARs [29].
In a subsequent work on compound 8 derivatives, the role
of different 5-furan ring substituents towards selectivity and
affinity for α1-AR subtypes was explored. To this end, substit-
uents with different electronic and/or lipophilic properties
like bromine, methyl, methoxy or acetyl, were chosen (see
399
 Recent advances in the design and synthesis of prazosin derivatives

NH2
O
N

O
O N N N O
N O O N
N S
O O R
R 28a R = 3-Ph
28b R = 4-Ph

NH2
HO ( )
O n NH2
N S S
O O
N
O N N O
N O N N
N ( )
O n
1 S
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29 n = 4 O S
30 n = 1
31 n = 0
O

NH2
O
N O

O O N N
N

32 O O

Figure 5. Hybrid 1-related derivatives 28 – 32.

compound 13 for a general structure – Figure 1). All of the
new designed compounds maintained the α1b-AR selectivity,
although it was lower than that of compound 8 [30].
As increasing the number of contacts between the ligand
and its receptor would hopefully increase subtype selectivity,
the furan ring of prazosin and compound 9 and its carbon
analogue 7 was replaced by a phenyl ring (14), thus offering
the possibility of incorporating additional structural elements
at different positions (Figure 4). Interestingly, the structural
modifications performed did not improve affinity for α1-AR
subtypes; however, importantly, they did give rise to selectiv-
ity [23,31]. Moreover, a most intriguing finding was the obser-
vation that the insertion of a diaminohexane chain on the
benzene ring did not induce negative interactions with the
receptor, thus opening the path for the development of new
quinazolines bearing a polyamine backbone. On the basis of
these results, hybrid tetra-amine disulfides were synthesised by
combining the structural features of prazosin or compound 7
and benextramine 15, an irreversible α1/α2-AR antagonist.
With the aim of verifying the role of the disulfide moiety of
the latter on the interaction with α1-AR subtypes, the corre-
sponding carbon analogues were included in the study. Of the
synthesised compounds (16 – 27), quinazolines that lacked the
disulfide bridge behaved, like prazosin, as competitive antago-
nists, whereas all the polyamine disulfides displayed a nonho-
mogeneous mechanism of inhibition at the three subtypes as
they were, like compound 15 noncompetitive antagonists at
the α1a- and α1b-AR subtypes. However, unlike compound
15, the polyamine disulfides were competitive antagonists at
the α1d-AR. These results may suggest the presence, in the
binding pocket of α1a- and α1b-ARs, of a suitable binding
thiol function that would experience an interchange reaction
with the disulfide moiety of the antagonist and which would
be missing, or not accessible, in the α1d-AR subtype [32].
An attractive strategy for new prazosin derivatives was
applied by Gasco et al. [33] to obtain antihypertensive agents
with two distinct vasodilation mechanisms: α1-AR
antagonism and nitric oxide (NO) mediated vasodilation [33].
For this purpose, some hybrid compounds were synthesised
by combining two pharmacophoric units, such as the quina-
zoline ring of prazosin and the NO-prodrug furoxan moiety
for the furanylcarbonyl function in prazosin. The
(furoxanylsulfonyl)piperidine derivatives 28a and 28b (Figure
5) showed NO vasodilation and α1-AR antagonism activities
in an appropriate balance.
Following an analogous approach, further modifications
were performed on the lead structure (1) with the aim of wid-
ening its biological profile. Thus, to generate antioxidant and

400 Expert Opin. Drug Discov. (2006) 1(5)

 Minarini, Bolognesi, Tumiatti & Melchiorre

Table 1. Affinity profile of compounds 29 – 32 at α1-AR subtypesa.

NH2 NH2
O O
N N

O N N O N N O
N (CH2)n N
S S
O 32

29 – 31
O

No n pKB or pA2 pKi

α1A α1B α1D α1a α1b α1d

1 8.93 ± 0.10 9.06 ± 0.11 8.93 ± 0.10 9.23 9.39 9.65
29 4 7.19 ± 0.10 7.39 ± 0.12 7.92 ± 0.22 8.85 8.90 9.05
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30 1 9.00 ± 0.11 8.99 ± 0.21 9.04 ± 0.06 9.54 9.51 9.41

31 0 7.73 ± 0.05 8.76 ± 0.20 9.06 ± 0.06 9.09 9.27 9.31
32 7.62 ± 0.06 8.53 ± 0.12 9.07 ± 0.01 8.90 9.17 9.03
Lipoic acid <5 <5 <5

a Affinity constants, expressed as pK or pA (isolated tissues) or pK (Chinese hamster ovary cells) values.
B 2 i
Data from [34].

antiproliferative activities in the same molecule, the furoyl
moiety of prazosin was replaced either with the lipoyl frag-
ment of the well-known antioxidant lipoic acid (LA) (or its
lower homologues), or with 1,4-naphthoquinone, thereby
affording (29 – 31) and compound 32, respectively [34]
(Figure 5). In particular, the pharmacological profiles of com-
pounds (29 – 32) at α1-AR subtypes, evaluated by functional
and binding studies, were very promising in terms of both
affinity and selectivity (Table 1). Compounds 29 and 32 5were
able to protect prostate cells against reactive oxygen species
formation evoked by oxidative stress, indicating that antioxi-
dant properties were retained only by compounds that incor-
porated the 1,4-naphthoquinone and LA structure, but not
that of its lower homologues 30 and 31. In contrast to com-
pound 29, compounds 30 – 32 displayed an antiproliferative
activity higher than that of prototype prazosin [35]. This study
showed that it is possible to obtain multipotent drugs able to
display both a potent α1-AR antagonism and antiproliferative
activity combined with the capacity to inhibit oxidative stress.
The amino-quinazoline moiety of prazosin and its conge-
ners has also been modified by introducing a substituent on
the 4-amino group, leading to a series of compounds from
which FH-71 (33) and EW-154 (34) emerge for their selectiv-
ity for α1a- and α1b-ARs, respectively, in both functional and
binding experiments [36] (Figure 1).
As a consequence of the early evidence on the essential role
played by the piperazine ring, most of the quinazolines
described so far have been derived from modifications
performed at the piperazine and aromatic rings, keeping the
2,4-diamino-6,7-dimethoxyquinazoline portion unaltered.
However, the pharmacological data of some quinazo-
lin-4-(3H)-one derivatives, patented in recent years by phar-
maceutical companies [37], attested that structural variations
of the quinazoline ring can be successfully attempted. Com-
pound 35 displays very high antagonistic potency at the puta-
tive rabbit aorta α1L-AR subtype and is claimed to be useful
for treating BPH, sexual dysfunctions and hypertension. This
putative α1L-AR subtype, has been found in vascular and
lower urinary tract smooth muscle, and has been referred to as
α1L-AR because of its low affinity for prazosin. However,
some studies have reported the hypothesis that α1L-AR could
represent a functional phenotype of the α1a-AR subtype.
Other quinazolinone derivatives, exemplified by compound
36, are stated to be selective towards α1a/α1b-AR subtypes over
the α1d-AR subtype and are claimed for the treatment of BHP
with reduced side effects [37]. More recently, a series of 2-aryl
substituted quinazolinone derivatives of general formula 37,
emerged as α1a- and α1b-AR selective antagonists, particularly
when the R2 functional group is not hydrogen [101] (Figure 1).
Further modifications of the quinazoline substructure
were reported in a study describing the design, synthesis and
biological evaluation of a series of compounds where the
quinazoline moiety of prazosin was replaced with a tetrahy-
droacridine system. The constrained structure preserved the
N-1 basicity, but forced key features to assume a reciprocal
arrangement, probably similar to that of prazosin in one of

Expert Opin. Drug Discov. (2006) 1(5) 401

 Recent advances in the design and synthesis of prazosin derivatives

H
O NH2 1) NaOCN O N OH O N O

N NH
O COOH O O
2) HCl
OH O
40
41
PCl5
POCl3
O
HN N O
O N Cl O N Cl
NH3
1
N N
O O
NH2 Cl
43
42

Figure 6. Classical synthesis of 1.

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O NH2 N

1) (COCl)2 H H
O O O N N
N

OH O S
2) Bu4NNCS N C S O
O
44 45 46
O

N
O
N
H
N

H
N N
CF3COOH
1. CF3COOH O N
O
O
N

O
O
47

Figure 7. Synthesis of 1 by solid-phase approach.

its low-energy conformations. Despite the intriguing simi-
larity shown by prazosin and compound 38 with respect to
the relative positions of the pharmacophoric functions, the
overall series of derivatives was less potent in all the α1-AR
subtypes relative to prazosin, with most displaying a ten-
dency to selectivity for the α1b-AR subtype in both func-
tional and binding experiments. This finding suggests that
the newly introduced tricyclic system represents an
interesting pharmacophore at the α1b-AR subtype, leading
to a significant affinity, which does not seem to be influ-
enced by the nature of a lateral chain [38].
Finally, in 2006, some imidazo[5,1-b]quinazolines linked
to aryl piperazines, exemplified by the general structure com-
pound 39 (Figure 1) were synthesised as prazosin-constrained
analogues and proved that the structure–activity relationship
for α1-AR antagonists (hypotensive activity) included the

402 Expert Opin. Drug Discov. (2006) 1(5)


Cl
O
N
R'
O N Cl
NH O R 2R 3 N
R'
O N
48 49
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Figure 8. Solid-phase approach for the synthesis of a 2,4-diaminoquinazoline library.
absence of any substituents at the phenyl group of the
arylpiperazine moiety and had no branching at the oxoethyl
linker. Unfortunately, data on subtype selectivity of the syn-
thesised compounds were not reported [39].
3. Synthesis of prazosin derivatives
Due to the importance of quinazoline derivatives for the
pharmaceutical community and in parallel with the search
for new lead compounds, many research efforts have been
devoted to developing readily accessible and efficient
synthetic methodologies.
The first synthesis of prazosin, was described by Hess
et al. [102]. Prazosin (1) was prepared by the cyclisation of the
ureido derivative of the 6-aminoveratric acid (40) with
sodium or potassium cyanate in acidic aqueous media. The
resulting 2,4-dihydroxy-6,7-dimethoxyquinazoline (41) was
chlorinated at the 2- and 4-positions with a mixture of phos-
phorus pentachloride and phosphoryl chloride. By reacting
with an excess of ammonia in tetrahydrofuran, the resulting
2,4-dichloroquinazoline (42), was converted in
2-chloro-4-aminoquinazoline (43). Finally, the chloro
derivative was condensed with 1-(2-furoyl)piperazine to
generate prazosin (Figure 6).
A more recent approach to the synthesis of quinazoline
derivatives is represented by solid-phase and combinatorial
methodologies. These innovative techniques allowed an
intense production of several libraries based on the
Expert Opin. Drug Discov. (2006) 1(5)
Minarini, Bolognesi, Tumiatti & Melchiorre
R'
N
N
O
N
N
R2
O N N
Cl
R3
50
CF3COOH
R'
NH
O
N
R2
O N N
R3
51
quinazoline nucleus, exhaustively reviewed by Vogtle [40]. The
authors limit their report to the synthesis of the
2,4-diaminoquinazoline scaffold, and in particular, to the
solid-phase synthesis of prazosin, but several other methods
associated with the synthesis of other quinazoline-related
nuclei are present in the literature. Wilson [41] reported the
solid-phase synthesis of 2,4-diaminoquinazoline, starting
from an acylisothiocyanate resin (45) and generated from
carboxy polystyrene (44). Resin (45) was condensated with
2-amino-4,5-dimethoxybenzonitrile and subsequently treated
with 1-(2-furoyl)-piperazine to give the guanidine derivative
47, which was treated with trifluoroacetic acid to afford
prazosin with a yield of 70% (Figure 7).
A more general and versatile method was described by Dhanoa
et al. [42] and later slightly modified by Dener et al. [43]. The start-
ing material was represented by polymer bound amines (48)
which reacted with 6,7-dimethoxy-2,4-dichloroquinazoline fol-
lowed by an aromatic nucleophilic substitution with the appro-
priate amine and subsequent cleavage to give the desired
quinazoline (51) (Figure 8)
A modified synthesis of the antihypertensive agent iodoazi-
doarylprazosin (52) [44] (Figure 1) has been published recently.
Compound 52 is a prazosin derivative shown to function as a
multi-drug-resistance reversal agent and used as a standard
photo-affinity label for competition assays on P-glycoprotein.
The newly developed convergent route to compound 52
involved a direct addition of an acylated piperazine
intermediate to the 2,4-dichloroquinazoline. Moreover,
403
 Recent advances in the design and synthesis of prazosin derivatives
palladium imidazolium heteroatom coupling was also
investigated as an alternative and more efficient route to
obtain 6,7-dimethoxy-2-piperazin-1-yl-quinazo-
lin-4-ylamine, a useful intermediate in the preparation of pra-
zosin derivatives.
4. Conclusion
Although some of the early α1-AR antagonists are still used in
the treatment of hypertension, the newly disclosed com-
pounds are mainly used in urological pathologies. Through
the developments of some of the most potent, selective and
widely used α1-AR antagonists structurally related and unre-
lated to prazosin, the past 10 years have seen considerable
gains in understanding the role of α1-ARs in the aetiology of
LUTS/BPH. As a result, more uroselective and less vasoactive
α1-AR antagonists such as compound 4 have been developed.
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A wealth of evidence has established the α1-AR antagonists to
be clinically effective in relieving the symptoms associated
with BPH by relaxing prostatic smooth muscle tone. More
recently, α1-AR antagonists were found to be useful in
increasing the frequency of spontaneous passage of the distal
ureteral calculi [45]. However, this action alone does not fully
account for the long-term clinical response to these drugs in
BPH patients. Furthermore, the advances in understanding
the molecular mechanism governing prostate cell proliferation
have led to the identification of possible novel effects of
quinazoline derivatives against prostate cancer growth. Exper-
imental clinical studies have provided new evidence to sup-
port a differential growth-suppressing function of the α1-AR
antagonists against prostate cancer, that is independent of an
α1-AR mechanism [46]. The quinazoline-based antagonists 2
and 3 suppress prostate growth by inducing apoptosis and
preventing cell invasion and migration of prostate tumour
epithelial cells and vascular endothelial cells. Differently, tam-
sulosin, an α1-AR antagonist clinically effective for BPH
treatment, fails to exert a similar apoptotic action, indicating
that this effect is mediated by the quinazoline nucleus [47].
This and other evidence challenges conventional knowl-
edge of the mechanism of action of α1-AR antagonists, and
points to a new therapeutic value for these drugs by provid-
ing a differential molecular basis for their antitumour effi-
cacy. In 2005, it was found that compound 2 gives rise to an
apoptotic/anti-angiogenic effect in transitional cell
carcinoma of the bladder, similar to the effect seen in
prostate cancer [48].
A 2004 study demonstrated that three derivatives could
be pharmacologically exploited to develop a novel class of
anticancer agents that mediate apoptosis in PC-3
androgen-independent prostate cancer cells through the
inhibition of intracellular protein kinase B/Akt activation.
The apoptosis-inducing activity of compound 3 was further
optimised by replacing the (2,3-dihydro-benzo[1,4]diox-
ane)-carbonyl moiety with aryl-sulfonyl functions, thus
highlighting the translational potential of these agents in
404 Expert Opin. Drug Discov. (2006) 1(5)
prostate cancer prevention and therapy [49]. It is plausible
that quinazoline-based derivatives, through competing
with ATP binding, interfere with an as yet, unidentified
tyrosine kinase that uses Akt as an effector. It is worth not-
ing that these compound 3-derived agents are structurally
distinct from the quinazoline-based inhibitors of epidermal
growth factor receptor (EGFR) tyrosine kinases such as
erlotinib and gefitinib. These two anilinoquinazoline
derivatives recently approved for the second- and third-line
treatment of non-small-cell lung cancer, act as EGFR tyro-
sine kinase inhibitors and compete for the ATP-binding
site in the intracellular domain, inhibiting EGFR auto-
phosphorylation. This strategy for developing targeted
anticancer therapy has become more important than the
optimisation of therapy with conventional anticancer
drugs [50,51].
Further support for the multiple biological actions of
quinazoline derivatives comes from the discovery of a series of
anilinoquinazolines, previously described as competitive
inhibitors at the ATP site of EGFR tyrosine kinase, which
showed allosteric inhibition of fructose 1,6-bisphosphatase
(F16Bpase). Selective inhibition of this enzyme was obtained
through the addition of appropriate polar functional groups
at the quinazoline 2-position, thus separating the F16Bpase
inhibitory activity from the EGFR tyrosine kinase activity
previously observed. An F16Bpase inhibitor should reduce
hepatic glucose output and lower blood glucose by inhibiting
the elevated rate of gluconeogenesis present in diabetic
patients and would, thus, be a useful therapeutic tool for the
treatment of type 2 diabetes [52].
Finally, as recently as 2006, a patent reported the design
and synthesis of some 2-amino-3,4-dihydroquinazoline
derivatives that are useful in the treatment of Alzheimer’s
disease as enzyme β-secretase (BACE) inhibitors [103].
5. Expert opinion
The effort to design and synthesise agents selective for each
of the three α1-AR subtypes is still an active area of research
in medicinal chemistry. Due to a high percentage of amino
acids that are identical in the active binding pocket of the
different α1-AR subtypes and despite the impressive results
obtained by molecular biology studies, the availability of
selective ligands that are able to recognise only one among
the α1-AR subtypes, is limited. The picture is further com-
plicated as it is still unclear whether most of the so-called
competitive antagonists are neutral antagonists or inverse
agonists [53] and whether or not constitutively active native
receptors have any physiological or pathological significance.
Recent experimental evidence suggests that a large number
of structurally different α1-AR antagonists, including quina-
zolines, are inverse agonists at both α1a- and α1b-AR
subtypes (and this finding should explain the unwanted
effects in vivo on the cardiovascular system such as orthos-
tatic hypotension) [54]. The distinction of receptor antago-
 Minarini, Bolognesi, Tumiatti & Melchiorre

nists as inverse agonists versus neutral antagonists will allow
a better interpretation of the pharmacological effects of clin-
ically used drugs with respect to their mechanism of action.
Unfortunately, as spontaneous activity of receptors in vivo is
difficult to assess, the therapeutic implications for the use of
inverse agonists versus neutral antagonists remain a matter
of debate.
As detailed in the Section 4, it is well known that,
besides the essential role played by the
2,4-diamino-6,7-dimethoxy-quinazoline moiety for α1-AR
antagonism, the quinazoline ring is a heterocyclic motif
that is found in a broad variety of biologically active com-
pounds that hit different pharmaceutical targets.
Therefore, it meets the requirements of a privileged struc-
ture that is, ‘a single molecular framework able to provide
ligands for diverse receptors’ [55]. As it is difficult to reach
lead discovery or optimisation without combinatorial
methodologies, the solid-phase synthesis of a privileged
structure or substructure based on quinazoline could pro-
vide a way of generating numerous lead compounds for a
variety of receptor and enzymatic targets, including the
α1-AR [56].

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Patents
101. FHOFFMAN-LA ROCHE AG:
WO2005395 (2005).
102. PFIZER: US3511836 (1970).
103. JANSSEN PHARMACEUTICA NV:
WO2006024932 (2006).
Affiliation
Anna Minarini†, Maria Laura Bolognesi,
Vincenzo Tumiatti & Carlo Melchiorre
†Author for correspondence
Department of Pharmaceutical Sciences,
University of Bologna, Via Belmeloro 6,
40126 Bologna, Italy
Tel: +39 0512099709; Fax: +39 0512099734;
E-mail: anna.minarini@unibo.it
407