Design and Synthesis of Novel Antihypertensive Drugs P. Moutevelis-Minakakis, a M. Gianni, a H. Stougiannou, a P. Zoumpoulakis, b A. Zoga, b A. D. Vlahakos, c E. Iliodromitis d and T. Mavromoustakos b, * a University of Athens, Department of Chemistry, Zographou 15771, Athens, Greece b Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Athens, Greece c Aretaieo University Hospital, Division of Nephrology, Athens University, Medical School, 76 Vas. Sofias, Ave, 11528 Athens, Greece d Onassis Cardiac Surgery Center, 356 Sygrou Ave., Athens, Greece Received 7 January 2003; revised 21 February 2003; accepted 27 February 2003 Abstract—AT1 antagonists constitute a new generation of drugs for the treatment of hypertension and are designed and synthe- sized 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 His 6 -Pro 7 -Phe 8 part of Ang II and is based on 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 estimated that 20% of the Greek popula- tion suffers from hypertension. 1 À3 Research efforts for the controlling of hypertension are focused in blocking Ang II release and more recently in competing Ang II binding on AT 1 receptors. This latest approach gener- ated the synthesis of losartan and promoted it in the pharmaceutical market (COZAAR). Other derivative drugs which fall into SARTAN’s class followed. 2,3 To comprehend the 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, AT 1 non-peptide antagonists commercially available as well as synthetic ones were explored. AT 1 antagonists are designed to mimic the C-terminal part of Ang II. 4 In this aspect, it is proposed that 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 His 6 . This mimicry can be revised if future literature 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 Based on these superimposition studies and the model proposed of sarmesin we synthesized (5S)-1- benzylo-5-(1H imidazol-1ylo-methylo-)-2-pyrrolidinone (MM1) and we analyzed its 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 complicated structure with additional features (i.e., butyl chain, hydroxymethyl group and tetrazole). MM1 is a simple molecule which has characteristics of the C-terminal of sarmesin and it is designed to mimic conformational characteristics of His 6 -Pro 7 -Phe 8 . 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 lead com- pound and many others have been designed and are in the process of being synthesized. It has significant anti- hypertensive activity (71% compared to losartan) as it is shown in Figure 2. 0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0960-894X(03)00251-8 Bioorganic & Medicinal Chemistry Letters 13 (2003) 1737–1740 *Corresponding author. Tel.: +30-1-0727-3869; fax: +30-1-0727- 3831; e-mail: tmavro@eie.gr