Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi-targeted ligands for α1- and AII-receptors antagonism

Article abstract of DOI:10.1016/j.bmcl.2013.04.054

Multiple-targeted ligands can have certain advantages for the management of hypertension which has multiple controls. Molecules with dual bioactivities are available in literature for treating metabolic disorders like diabetes, hypertension and hypercholesterolemia. After scrutinizing the SAR of prazosin-type α₁-blockers and AII-antagonists it was planned to develop dual α₁- and AII-antagonists. Five series of quinazoline derivatives were synthesized and evaluated as dual α₁- and AII-antagonists on rat aortic strips for the blockade of known α₁- and AII-agonist mediated contractions. Many compounds showed balanced activity on both the receptors but compound (22) was found to be the most active derivative having higher antagonistic activity on both the receptors. In the in vivo experiments the chosen compound (22) was slightly less active than prazosin but was found to be equipotent to losartan. These findings shed a new light on the structural requirements for both α₁- as well as AII-receptor antagonists.

Full text of DOI:10.1016/j.bmcl.2013.04.054

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3959–3966
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi-
targeted ligands for a1- and AII-receptors antagonism
⇑
M. R. Yadav , P. P. Naik, H. P. Gandhi, B. S. Chauhan, R. Giridhar
Pharmacy Department, Faculty of Tech. & Engg., The M.S. University of Baroda, Vadodara 390001, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 December 2012
Revised 1 April 2013
Accepted 19 April 2013
Available online 30 April 2013
Multiple-targeted ligands can have certain advantages for the management of hypertension which has
multiple controls. Molecules with dual bioactivities are available in literature for treating metabolic dis-
orders like diabetes, hypertension and hypercholesterolemia. After scrutinizing the SAR of prazosin-type
a
1-blockers and AII-antagonists it was planned to develop dual
nazoline derivatives were synthesized and evaluated as dual
for the blockade of known 1- and AII-agonist mediated contractions. Many compounds showed balanced
a
1- and AII-antagonists. Five series of qui-
a
1- and AII-antagonists on rat aortic strips
a
Keywords:
Multiple-targeted ligands
Quinazoline
Dual inhibition
Prazosin
Losartan
activity on both the receptors but compound (22) was found to be the most active derivative having
higher antagonistic activity on both the receptors. In the in vivo experiments the chosen compound
(22) was slightly less active than prazosin but was found to be equipotent to losartan. These findings shed
a new light on the structural requirements for both
a
1- as well as AII-receptor antagonists.
Ó 2013 Elsevier Ltd. All rights reserved.
Hypertension
It is increasingly being recognized that a balanced modulation
of multiple targets can provide a superior therapeutic efficiency
in comparison to targeting a single enzyme/receptor in a diseased
state.1 There is no single drug treatment of hypertension due to dif-
ferences in etiology, risk factors and body constitution of individu-
als.2 It requires a combination therapy as a single drug of any class
of antihypertensives proves ineffective.3,4 The conventional treat-
ment of hypertension involves combination of drugs from such
designing approaches, in which structural features of selected
ligands are combined into one single entity, have produced new
ligands that act on a variety of targets. A key challenge in the
designing of such multiple-targeted ligands is attaining a balanced
activity at each target of interest while achieving a higher selectiv-
ity and a suitable pharmacokinetic profile simultaneously.8 The so
called dual acting drugs (dimeric ligands) are designed by joining
together the pharmacophores by a cleavable/noncleavable linker
or more commonly by overlapping the pharmacophores of two
drugs into a single chemical entity by taking advantage of common
structural features of two or more classes of drugs. To integrate the
pharmacophores of two drugs common structural features of both
of the drugs are overlapped.
categories of drugs as diuretics,
a1-adrenergic receptor antago-
nists, b-blockers, calcium channel blockers, ACE inhibitors, AII-
receptor antagonists etc.
Compared to drug combinations, there are certain advantages
associated with a multiple-targeted ligand as a therapeutic agent,
such as more predictable pharmacokinetic and pharmacodynamic
relationship and improved patient compliance as a consequence
of administration of a single drug at a time. It is interesting to note
that of the known multiple targeted (multi-action) drugs only a
few have been designed to act on the intended targets. Rest others
have been serendipitously discovered wherein the modes of action
of the drugs were elucidated retrospectively to be multiple tar-
geted. Increase in the number of publications on the designing
and development of multiple targeted molecules in recent times
is an indication of developing interest in the field.5–7 Rational
There are numerous examples of hybrid molecules wherein
dual bioactivities have been packed into a single chemical entity.
Glitazones (insulin sensitizers) and fibrates (lipid lowering agents)
act through PPARc and PPARa receptors respectively. The arylox-
azole (1) is a combination of thiazolidinedione derivative (2) and
fenofibric acid9 (3). A dual acting hybrid sulphonamide (4) was ob-
tained by linking propranolol, a b-blocker with mefruside, a diure-
tic.10 In prizidilol (5), hydralazine a well known vasodilator was
integrated with a pharmacophoric group responsible for b-block-
ing activity to afford a dual acting drug.11
⇑
Corresponding author. Tel.: +91 265 2434187; fax: +91 265 2418927.
E-mail address: mryadav11@yahoo.co.in (M.R. Yadav).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.04.054

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M. R. Yadav et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3959–3966
imidazole nucleus with other heterocyclicring systems, replace-
ment of the biphenylmethyl side chain with smaller and bigger
groupings, and replacement of tetrazole moiety with other acidic
groups. So, it was planned to design hybrid structures by employ-
ing 6,7-dimethoxyquinazoline ring skeleton as the common struc-
tural motif for a1 as well as AII antagonism and attaching various
types of side chains at its 2-and/or 3-positions. The main obstacle
in the selection of the side chain was the nature of the side chain
grouping—whether the attached side chain should have acidic
Me
O
COOH
Me
O
N
Me
O
(1)
O
Cl
O
COOH
Me
Me
O
NH
Me
S
O
N
O
O
functionality or a basic one because prazosin-type of
a1-blockers
(2)
(3)
contained basic groupings in the side chain while all reported AII
antagonists had an acidic functionality in the side chain. It was
envisaged to make a try with all the three types of functional
groups, acidic, basic as well as neutral in the attached side chain
for designing of the compounds. Assuming a high degree of struc-
tural tolerance for antagonistic activity by both the receptors, the
given five types (A–E) of compounds were designed:
Cl
NHNH2
H
N
N
N
O
N
H
S
SO2NH2
O
O
OH
OH
H
O
N
Me
Me
Me
(4)
(5)
O
Several experimental and clinical studies have pointed towards
the linked action of RAAS (renin angiotensin aldosterone system)
and SNS (sympathetic nervous system) in the homeostatic control
of cardiovascular functions.12,13 Evidences show that these two
systems interact mutually with each other to effect their cardio-
vascular regulatory roles.14,15 Stimulation of SNS results into vaso-
constriction and increased inotropic and chronotropic effects of
heart while stimulation of RAAS results in increased production
of active hormone angiotensin II (AII) which raises blood pressure.
The RAAS–SNS interactions have physiological as well as patho-
physiological relevance; a reciprocal reinforcement of the favor-
able as well as unfavorable cardiovascular, renal, metabolic and
reflex effects of the two systems have been reported in a variety
of cardiovascular conditions like hypertension.15–17 SNS and RAAS
become important targets in order to control the blood pressure as
both of the systems work in coordination. Simultaneous blockade
of both the systems should prove to be beneficial in the manage-
ment of hypertension. Two important targets belonging to the
MeO
O
N
Me
X
H
N
MeO
MeO
N
MeO
N
X
Me
N
(A)
(B)
O
N
MeO
MeO
N
Me
N
X
N
(C)
NH2
NH2
MeO
MeO
MeO
N
N
X
H
N
N
N
MeO
N
N
n
X
n
(n = 0,1)
(D)
(E)
RAAS–SNS systems are the
1-adrenergic receptor blocking agents and AII receptor antag-
onists both are important classes of antihypertensive drugs. A wide
variety of chemical structures18 possess
1-adrenoceptor blocking
activity. Similar observations have been made for AII receptor
antagonists.19 After studying the structure activity relationships
of both the classes of drugs minutely, it became evident that the
drug binding sites of both the receptors could accommodate wide
structural variations in the active molecules. And if that presump-
tion was correct, then designing of dual acting a1 and AII antago-
nists should not be a distant dream.
a1- and AII receptors.
a
Work was initiated for the preparation of series A compounds. For
synthetic convenience, compounds with neutral groups like CH3,
OCH3, Cl, Br, NO2, CN etc. at different positions of the phenyl ring
were prepared first. Compounds so synthesized (Scheme 1) were
screened for obtaining preliminary biological data. The results of
this preliminary biological screening were a bit shocking to us.
Surprisingly, all of the screened compounds showed dual antago-
nism to the phenylephrine and AII responses in the in vivo normo-
tensive rat model; although the level of antagonism was low to
moderate in comparison to prazosin and losartan, the two proto-
type lead antagonists. In vitro experimentation on isolated rat aor-
tic strip could not be performed for these neutral compounds due
to their solubility problem in aqueous solutions. These results
forced us to have a relook at the mechanism of antihypertensive
actions of both prazosin and losartan. When neutral molecules
a
Prazosin (6), an important
molecule. Not many structural changes have been carried out in
prazosin type of 1-blockers except for some variations in the side
a1-blocker was chosen as the lead
a
chain at position-2 of the quinazoline ring system. On the other
hand, by considering losartan (7) as the lead molecule of AII antag-
onists, it was noted that too many structural changes have been
performed to obtain potent AII antagonists, like replacement of
without any characteristic side chains could show dual
a1- and
AII-receptor antagonism, was it possible for prazosin and losartan
also to show dual antagonism at both the receptors? pA2 value
determinations of both of the standard lead molecules confirmed
the correctness of our assumption of wide structural tolerance by
both the receptors in their active spaces—prazosin exhibited po-
Cl
N
Me
OH
NH2
N
N
N
tent dual antagonism at
(pA2 8.26) (Table 1) while losartan was found to be a potent antag-
onist at AII-receptor (pA2 8.08) but a poor (pA2 5.46) one at a1
a1- (pA2 8.91) as well as AII-receptors
MeO
MeO
N
NH
N
-
N
N
N
O
receptor when evaluated on rat aortic strip using phenylephrine
O
and AII as agonists.20
(6)
(7)

M. R. Yadav et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3959–3966
3961
NH2
MeO
MeO
N
H
N
X
N
(vii)
NH2
(D; n=1)
MeO
MeO
CN
MeO
MeO
(vi)
N
Cl
NO2
N
(e)
(viii)
NH2
N
(f)
MeO
MeO
N
X
N
(v)
R=H
N
(E; n=1)
O
O
O
MeO
MeO
MeO
MeO
MeO
MeO
R
(i)
(iv)
OH
NH2
OH
NO2
N
H
NO2
(b)
(d)
(a)
(ii)
(ix)
O
O
N
O
MeO
MeO
MeO
MeO
R
N
H
Me
NH
N
(x)
H
Me
MeO
NH
MeO
NH2
Cl
(c)
(g)
O
(iii)
(h)
(xii)
R=H
(xi)
O
X
Cl
MeO
MeO
O
N
N
MeO
MeO
MeO
MeO
N
Me
N
Me
N
(A)
Cl
N
Cl
(j)
(vii)
(i)
O
MeO
MeO
(xiii)
NH2
N
Me
(viii)
H
N
O
N
MeO
MeO
X
MeO
MeO
N
N
Me
(B)
X
N
Cl
N
N
N
(k)
(C)
(viii)
N
NH2
(vii)
MeO
MeO
N
NH2
X
MeO
MeO
N
N
N
X
N
N
H
(E; n=0)
(D; n=0)
Scheme 1. Synthetic steps for various compounds (series A–E). Reagents: (i) H2, Pd/C; (ii) CH3CH2CH2COCl, NH4OAc; (iii) Br-CH2-C6H4X; (iv) SOCl2, n-BuNH2/NH3 (v) POCl3;
(vi) (a)-Fe, NH4Cl; (b)-ClCH2CN, HCl; (vii) H2N-C6H4X; (viii) 4-Piperazine-C6H4X; (ix) Fe, NH4Cl; (x) ClCH2COCl; (xi) KTB (xii) Urea, HCl; (xiii) NH3.
Buoyed by these results a large number of compounds represent-
ing all of the above described five categories of chemical structures
were synthesized (Scheme 1). The synthesized compounds were
evaluated on rat aortic strip for their pA2 value determinations using
the 2-n.butyl-3-benzyl substituted derivatives m-cyano (8) and m-
tetrazoly1 (9) derivatives were found to be the most active com-
pounds. Introduction of basic nitrogen in the side chain at
position-2 of the 4-quinazolinones improved a1-antagonistic activ-
phenylephrine and AII as agonists for
a
1- and AII receptors respec-
ity. Compound (11) was found to be the best among them having a
balanced activity at both the receptors but it was somewhat less po-
tent than prazosin (6). Restoring 4-amino group (as existed in pra-
zosin) from the 4-keto function improved the activity profile of
the synthesized derivatives. In the D-series, compounds with one
tively. The results are described in Table 1. 4-Quinazolinonoes
belonging to series (A–C) did not yield much promising dual inhib-
itors. 3-n.Butyl substitution yielded more potent compounds (10
and 11) than the 2-n.butyl substituted derivatives (8 and 9). Among

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M. R. Yadav et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3959–3966
Table 1
pA2 values of the prominent synthesized compounds on rat aortic strips
Compd
Structures
pA2 values
1-Receptor
a
AII-receptor
––
6
7
Terazosin
Prazosin
Losartan
8.65 0.37
8.08 0.11
5.46 0.41
6.39 0.40
8.26 0.10
8.43 0.21
CN
O
N
MeO
MeO
8
9
6.88 0.13
6.65 0.09
N
Me
N
N
N
NH
O
7.10 0.12
7.03 0.12
MeO
N
N
Me
Me
MeO
MeO
N
O
H
N
10
7.45 0.16
6.14 0.14
COOH
MeO
N
O
MeO
MeO
CN
N
Me
11
12
7.71 0.01
8.53 0.12
7.41 0.10
7.65 0.09
N
N
N
NH2
MeO
MeO
Me
N
N
N
H
NH2
MeO
MeO
N
H
N
13
14
9.87 0.15
8.37 0.43
N
NH2
MeO
MeO
N
H
N
8.37 0.27
7.07 0.16
N
NH2
MeO
MeO
N
H
N
15
16
17
9.38 0.18
8.09 0.12
6.86 0.12
7.64 0.07
9.04 0.15
10.64 0.10
N
NO2
NO2
NH2
MeO
MeO
N
H
N
N
NH2
MeO
MeO
N
H
N
N
COOMe

M. R. Yadav et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3959–3966
3963
Table 1 (continued)
Compd
Structures
pA2 values
a1-Receptor
AII-receptor
NH2
MeO
MeO
N
18
19
20
9.23 0.12
5.75 0.07
5.08 0.08
3.31 0.13
N
N
N
N
N
N
N
N
N
Me
NH2
MeO
MeO
N
10.41 0.12
8.74 0.08
Me
N
NH2
MeO
MeO
N
N
NH2
MeO
MeO
F
N
21
22
10.51 .014
10.10 0.20
5.52 0.10
8.83 0.04
N
NH2
NC
MeO
MeO
N
N
N
N
carbon linkage between the quinazoline ring and the basic nitrogen
offered more potent compounds than those in which nitrogen was
directly linked to the quinazoline nucleus. One such compound hav-
ing the highest activity was the p-tolyl derivative (12) which was al-
most equipotent to prazosin. Among the anilinomethyl analogs
large variations in the substituents were tolerated for potent activ-
ity against both the receptors. With the introduction of a methylene
group in between the amino and the quinazoline nucleus, antago-
nistic potency increased against both the receptors. An unsubstitut-
To corroborate the results obtained from experimentations on
isolated rat aortic strips, it was planned to evaluate the most active
compound from series E (22) in the in vivo studies. Compound (22)
was evaluated for its ability to inhibit the pressor responses in-
duced by phenylephrine (6 lg/kg, iv bolus) and AII (6 lg/kg, iv bo-
lus) in anesthetized normotensive rats. The effects are summarized
in the Figure 1. The results demonstrated that compound (22) has
dual inhibitory action upon pressor responses induced by agonists,
phenylephrine and AII. Thus, compound (22) has independently
shown dual-inhibiting potential to antagonize the effects of endog-
enous pressor substances like noradrenaline and AII. But the re-
sults of this comparative study were somewhat not as per
expectations, given the potent in vitro activity exhibited by com-
pound (22) on isolated aortic strips. Administration of compound
(22) on equimolar basis had only a modest inhibitory response at
the most when compared to the pressor-response inhibition med-
iated by the standard drugs prazosin or losartan. Since compound
(22) shows dual action, it was speculated that the actual concen-
tration of the compound reaching at a particular receptor could
be much lesser while administering it on a molar basis. The reason
for such an abridged response could be the distribution of the drug
upon both the receptors in question suggesting that only a fraction
of the compound (22) is available at a given time to act upon a par-
ticular population of receptors. This speculation is based on in vitro
studies performed earlier on isolated rat aortic strips. In these
experiments, compound (22) showed competitive antagonism
against phenylephrine and angiotensin II, respective specific ago-
ed phenyl ring (13) offered the most potent
a1-blocker while p-
methylcarboxylate group yielded the most potent (17) AII antago-
nist in the series.
Direct attachment of piperazine ring as it existed in prazosin, in
the E-series of compounds, increased the potency against the a1
-
receptors. But these compounds (18–21) started showing imbal-
ance in potency against both the receptors. Potency against the
a
1-receptor increased but the potency declined against the AII
receptor. Compound21 (21) was about 100 times more potent than
prazosin on 1-receptor but was poorly active against the AII
a
receptor. Introduction of methylene group in-between the pipera-
zine and quinazoline rings gave the most useful compounds. o-Cy-
ano substituted compound22 (22) was found to be the most useful
compound amongst the whole lot as it showed potent activity
against both the receptors.
Biological data of the synthesized compounds offered some
startling results as for as the existing knowledge about a1-receptor
blocking and AII antagonist drugs are concerned. The results
showed that it was not at all necessary to have an acidic side chain
to obtain a potent AII antagonist even a neutral group like CN in
compound (22) offered a potent AII antagonism. 4-Aminoquinazo-
lines in general yielded much more potent and balanced com-
nists of the
a1- and AII-receptors. This is evident from the right-
ward parallel shift observed in the dose–response plots for
compound (22). This competitive inhibition of the contractile re-
sponse in isolated vascular tissue shows that compound (22) has
the ability to bind to both the receptors in question in a dose-
dependent manner (Fig. 2). This condition of competitive binding
to both the receptors is expected to be prevalent in the in vivo
model also, thereby causing reduction in the inhibition response
pounds than 4-quinazolinones. Placing
a carbon linker in
between the quinazoline ring and the basic nitrogen offered more
potent and balanced dual acting compounds than directly linking
the basic nitrogen to the quinazoline ring.

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M. R. Yadav et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3959–3966
Figure 1. In vivo pressor inhibition effect of compound (22) on normotensive rats at two different doses in comparison to the standard drugs. Data is presented as
mean SEM of six animals.
of compound (22) on both the receptors in comparison to the stan-
dard drugs.
To provide credence to the above proposed hypothesis, it was
planned to evaluate the pressor-inhibition potential of compound
(22) under masked conditions. In vivo inhibition of phenylephrine
mediated arterial pressor response by compound (22) was mea-
sured in those animals in which 3.6 lM losartan was pre-adminis-
tered. The idea behind such a protocol was to mask the effects of
our compound (22) on AII receptor. Similarly, the other set in-
volved measurement of inhibition of AII mediated arterial pressor
response in those animals in which 0.72
lM prazosin was pre-
administered to mask the effects of compound (22) upon
a
1-recep-
tor. The standard drugs and the compound (22) were administered
at equimolar concentrations. The results obtained are shown in
Figure 3.
It can be observed that the hypothesis stands a chance as the
compound (22) was equipotent to losartan after masking the a1
-
receptors with prazosin but slightly less active than prazosin after
masking AII receptors with losartan. Slightly lesser activity of com-
pound (22) on a1-receptors could be due to differences in pharma-
cokinetic parameters from the standard drug prazosin. Predicted
plasma protein binding values for compound (22) and prazosin
are 97.5% and 96%, respectively, suggesting that plasma-protein
binding efficiency of compound (22) is slightly higher than prazo-
sin.23 To evaluate the degree of plasma protein binding, we tried to
compare the in vitro release profile of compound (22) and prazosin
from human plasma. For the plasma protein binding study, both
Figure 3. Evaluation of pressor response of compound (22) and prazosin for a1
antagonism (losartan was used for masking AII-receptors), and of compound (22)
-
and losartan for AII-antagonism (prazosin was used for masking of
equimolar concentrations (mean SEM of six animals).
a1-receptors) at
Figure 2. (a) Dose–response plot of compound (22) against phenylephrine on rat aortic strips. A rightward parallel shift of the curve can be observed in presence of
compound (22), n = 4. (b) Dose–response plot of compound (22) against angiotensin II on rat aortic strips. A rightward parallel shift of the curve can be observed in presence of
compound (22), n = 4.

M. R. Yadav et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3959–3966
3965
the drugs were spiked into blank human plasma and their release
through a semi-permeable membrane into physiological buffer
(phosphate buffered saline, pH 7.4) were compared over time. It
was observed that the release of prazosin is somewhat faster
(ꢀ10%) than that of compound (22) (Fig. 4). Assuming that this
would be true for the in vivo environment, then the amount of pra-
zosin reaching the receptor would be higher than compound (22),
which could account for the somewhat lesser response observed
with compound (22) in vivo. This could be observed from the
cumulative drug release profile shown below. Further, we have
also compared the release profile of losartan and compound (22).
Based on these studies, we excluded the possibility of differential
tissue distribution of compound (22) and losartan which was cor-
roborated by the inhibition of pressor responses of compound (22)
and losartan in the in vivo model.
Though compartmentalization of the drug was excluded with
the possibility of high-degree of plasma protein binding, the dis-
parity of receptor distribution cannot be ruled out. As stated above,
we have previously shown that prazosin shows potent antagonism
of the AII receptors as well.20 Such type of action is responsible for
an enhanced antihypertensive response afforded by prazosin.
However, this effect can play a dual role in our masking study,
Figure 5. Evaluation of pressor response of compound (22) and terazosin for a1
antagonism (losartan was used for masking AII-receptors to prevent binding of
compound (22) to AII-receptors), and of compound (22) and losartan for AII-
-
again by acting on both
the same study using terazosin as a standard
a
1 and AII receptors. Hence we performed
antagonism (terazosin was used for masking of
a
1-receptors to prevent binding of
compound (22) to
a1-receptors) at equimolar concentrations (mean SEM of six
a
1 antagonist (Fig. 5),
animals).
which we have shown to have negligible action on AII mediated
vascular smooth muscle contraction. Activity of terazosin is exclu-
sive for the a1 receptor and hence we can safely assume that the
effects of terazosin are mediated due to binding with a1 receptor
only. No significant differences could be observed between this
the leads to obtain more potent dual active compounds with bal-
anced activities on both of the targets.
study involving terazosin (as a masking agent and a standard a1
antagonist) and that of prazosin as shown in Figure 3.
-
Acknowledgements
To conclude, rational designing of hybrid molecules with bal-
anced biological activities on multiple targets can be a daunting
task. As mentioned earlier, there are few molecules that exhibit
such dual activity. In this paper, we have reported for the first time,
synthesis and biological evaluation of novel antagonists which
The authors acknowledge the financial support provided by the
Council of Scientific and Industrial Research (CSIR), New Delhi, In-
dia in the form of Senior Research Fellowship to H.G.
Supplementary data
have dual activity of antagonizing the a1- and AII-receptors simul-
taneously. Further investigations on these compounds are under-
way. These investigations include in vivo evaluation of active
compounds in rodent models of hypertension, identification of
their pharmacokinetic profile in rats, and further optimization of
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.
04.054.
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Figure 4. In vitro cumulative release profile of compound (22) in comparison to
that of prazosin hydrochloride and losartan potassium. All the compounds were
spiked in blank human plasma, filled in a semi-permeable dialysis bag which was
suspended in a beaker filled with physiological buffer maintained at 37 2 °C.
Samples were withdrawn at different time intervals (replacing equal volume of
buffer) and analyzed for drug contents by high performance liquid chromatography.
All studies were performed in triplicate.
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