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-
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00251-8