Design and synthesis of novel antihypertensive drugs

Article abstract of DOI:10.1016/S0960-894X(03)00251-8

AT1 antagonists constitute a new generation of drugs for the treatment of hypertension and are designed and synthesized to mimic the C-terminal segment of Angiotensin II (Ang II) and to block its binding action on AT1 receptor. For this reason, the conformational analysis of Ang II and its derivatives as well as the AT1 antagonists belonging to SARTANs class of molecules were studied. Such studies offer the possibility to reveal the stereoelectronic factors responsible for bioactivity of AT1 antagonists and to design and synthesize new analogues with better pharmacological and financial profiles. An example of a novel synthetic non-peptide molecule is given which mimics the His⁶-Pro⁷-Phe⁸ part of Ang II and is based on the (S)-pyroglutamic acid.

Full text of DOI:10.1016/S0960-894X(03)00251-8

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1737–1740
Design and Synthesis of Novel Antihypertensive Drugs
P. Moutevelis-Minakakis,a M. Gianni,a H. Stougiannou,a P. Zoumpoulakis,b A. Zoga,b
b,
A. D. Vlahakos,c E. Iliodromitisd andT. Mavromoustakos *
aUniversity of Athens, Department of Chemistry, Zographou 15771, Athens, Greece
bInstitute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Athens, Greece
cAretaieo University Hospital, Division of Nephrology, Athens University, Medical School, 76 Vas. Sofias, Ave, 11528 Athens, Greece
dOnassis Cardiac Surgery Center, 356 Sygrou Ave., Athens, Greece
Received7 January 2003; revised21 February 2003; accepted27 February 2003
Abstract—AT1 antagonists constitute a new generation of drugs for the treatment of hypertension and are designed and synthe-
sizedto mimic the C-terminal segment of Angiotensin II (Ang II) andto block its binding action on AT1 receptor. For this reason,
the conformational analysis of Ang II andits derivatives as well as the AT1 antagonists belonging to SARTANs class of molecules
were studied. Such studies offer the possibility to reveal the stereoelectronic factors responsible for bioactivity of AT1 antagonists
andto design andsynthesize new analogues with better pharmacological andfinancial profiles. An example of a novel synthetic
non-peptide molecule is given which mimics the His6-Pro7-Phe8 part of Ang II andis basedon the ( S)-pyroglutamic acid.
# 2003 Elsevier Science Ltd. All rights reserved.
Hypertension is a growing undesired symptom which
damages health and threatens mostly the developed
societies. It is estimatedthat 20% of the Greek popula-
tion suffers from hypertension.1À3 Research efforts for
the controlling of hypertension are focusedin blocking
Ang II release andmore recently in competing Ang II
binding on AT1 receptors. This latest approach gener-
atedthe synthesis of losartan andpromotedit in the
pharmaceutical market (COZAAR). Other derivative
drugs which fall into SARTAN’s class followed.2,3 To
comprehendthe stereoelectronic requirements which
may lead to the better understanding of the molecular
basis of hypertension, the stereochemical features of
angiotensin II, its peptide antagonists sarmesin and
sarilesin, synthetic peptide analogues, AT1 non-peptide
antagonists commercially available as well as synthetic
ones were explored. AT1 antagonists are designed to
mimic the C-terminal part of Ang II.4
shows unequivocally that AT1 antagonists possessing
tetrazole may anchor in a different aminoacid of AT1
receptor than C-carboxylate terminal of Ang II.3 At the
moment such definite evidence is lacking and drug
design can be based on the optimization of super-
imposition studies of losartan with C-terminal part of
sarmesin.5 Basedon these superimposition studies and
the model proposed of sarmesin we synthesized (5S)-1-
benzylo-5-(1H imidazol-1ylo-methylo-)-2-pyrrolidinone
(MM1) andwe analyzedits stereoelectronic properties
in comparison with losartan (Fig. 1).
Imidazole of MM1 mimics imidazole of losartan, pyrri-
lidinone, mimicks phenyl ring A and phenyl ring of
MM1 mimicks phenyl ring B of losartan. Losartan has
more complicatedstructure with aidtional features
(i.e., butyl chain, hydroxymethyl group and tetrazole).
MM1 is a simple molecule which has characteristics of
the C-terminal of sarmesin andit is designedto mimic
conformational characteristics of His6-Pro7-Phe8. MM1
is mounted into pyrrolidine scaffold. The pyrrolidinone
scaffold has already been used for the development of
CCK peptide mimetics.6 MM1 is the first leadcom-
poundandmany others have been designedandare in
the process of being synthesized. It has significant anti-
hypertensive activity (71% comparedto losartan) as it is
shown in Figure 2.
In this aspect, it is proposedthat the butyl chain of
losartan may mimic the isopropyl chain of Ile, the tet-
razole ring mimics the C-terminal carboxylate group
and the imidazole ring the corresponding imidazole ring
of His6. This mimicry can be revisedif future literature
*Corresponding author. Tel.: +30-1-0727-3869; fax: +30-1-0727-
3831; e-mail: tmavro@eie.gr
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00251-8

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P. Moutevelis-Minakakis et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1737–1740
Figure 1. Molecular structures of MM1 (left), sarmesin (middle), and losartan (right). The letters in the aromatic rings show their equivalency in the
design.
Therefore, a new avenue of candidate antihypertensive
drug is opened which uses a pyrrolidinone scaffold
insteadof a biphenyl ring. These molecules are advan-
tageous over the known SARTANs in two aspects: (a)
they are easily synthesizedand(b) their structures are
basedon conformational analysis of sarmesin andother
SARTANS. Such novel class of molecules further con-
The structure of MM1 was provedunequivocally using
1D and2D NMR COSY andNOESY spectroscopy.
Spectroscopic data for MM1 are provided in Table 1.
The most important NOEs for the MM1 showedthat
there is a spatial proximity between the two aromatic
rings. Protons of the phenyl ring are in a close distance
with proton 17,18. NOEs predict a close conformation
of the molecule. The use of conformational search pro-
cedures provided four low energy conformers (Fig. 4).
These four conformers have a diastereomeric relation-
ship (two enantiomeric pairs). The low energy con-
former best superimposedin the sarmesin supported
also all observedNOEs. The superimposition matched
the following equivalent groups: (a) imidazole group of
MM1 with imidazole group of His6; (b) phenyl group of
MM1 with phenyl group of Phe8; (c) lactame amide
group of pyrrolidinone with amide bond of Phe8-Pro7.
The superimposition was excellent (RMS=0.71 A) (Fig.
5, left). A superimposition of MM1 with losartan was
also achievedusing the following equivalent groups
(Fig. 5, right): (a) Phenyl rings B of MM1 andlosartan,
(b) carbonyl group of MM1 with tetrazole ring of
losartan, and(c) imidazole ring of MM1 with the cor-
responding imidazole ring of losartan (RMS=1.16 A).
firm our aromatic side-chain ring cluster model of Ang
7,8
II andsarmesin.
The simplicity of the synthesis of
MM1, a representative molecule of this class is shown in
Figure 3.
Conclusions
Figure 2. Adult nomotensive male New Zealand White Rabbits
weighing between 2.5 and3.3 kg were usedin this study. The animals
were anaesthetizedby pentobarbitone (30 mg/kg) via an ear vein,
intubatedandmechanically ventilatedwith 100% oxygen using a
respirator for small animals. The tidal volume was 15 mL and the rate
was adjusted to keep blood gases within normal range. Two poly-
ethylene catheters were inserted, one in the carotid artery for con-
tinuous bloodpressure monitoring via a transducer attachedto a
multichannel recorder and the other one in the jugular vein for angio-
tensin II administration. Angiotensin II dependent hypertension was
induced by infusing angiotensin II via a syringe pump at a constant
rate (0.08 mg/min). After the establishment of hypertension boluses of
the antagonist were given via the jugular vein andthe changes of
blood pressure were recorded. Angiotensin II and 0.0059 mol of the
antagonist were diluted in 5% dextrose.
The biological results for MM1 show that under-
standing of the stereoelectronic features responsible for
activity in sarmesin andAT antagonists may leadto
1
new classes of molecules with certain advantages over
the drugs already existing in the market. Their activity
will shedlight to the validity of the proposedmodels.
From the reportedmodels of Ang II there is no criterion
for favoring a certain conformation. To our opinion a
model is valuable if it aids to comprehend the pharmaco-
phore segments responsible for activity andhelps in the
design of new bioactive drugs. The model of Ang II

P. Moutevelis-Minakakis et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1737–1740
1739
Figure 3. Chemical synthesis of MM1.
Table 1. Assignment of proton andcarbon-13 NMR peaks
Carbon number
dH (m)
dc (ppm)
3
4
2
6
1.79, 2.13 (m)
2.34 (m)
3.79 (m)
3.94 (d), 5.08 (d)
4.04 (d)
6.81 (s)
7.12 (s)
7.25–7.35 (m)
7.25–7.35 (m)
7.40 (m)
7.41 (s)
21.94
28.70
56.42
44.49
48.27
129.76
118.79
128.50
127.59
127.59
137.04
135.52
174.57
13
17
18
8, 12
9, 11
10
15
7
—
—
5
Figure 4. Low energy conformers of MM1 derived using conforma-
tional search procedures: Monte Carlo and Molecular Dynamics.
These conformers were in agreement with NOEs observedusing 2D
NOESY experiments. The software usedto generate the conformers
was Quanta Charmm of MSI.
Figure 5. (left) Superimposition of MM1 with C-terminal segment of sarmesin (red); (right) superimposition of MM1 with losartan (yellow).

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7
proposedby J. Matsoukas andhis collaborators
appears to satisfy these criteria andit may serve to
design new antihypertensive molecules.
4. Fermandjian, S.; Sakarellos, C.; Piriou, F.; Juy, M.; Toma,
F.; Thanh, H. L.; Lintner, K.; Khoslia, M. C.; Smeby, R. R.;
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Mini Rev. Med. Chem. 2001, 1, 207.
6. Giannis, A.; Kolter, T. Angew, Chem. Int. Ed. Engl. 1993,
32, 1244.
References and Notes
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moustakos, T.; Makriyannis, A.; Yamdagni, R.; Wu, Q.;
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