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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Efficient Synthesis and Biological Evaluation of Imidazole AT1Ang II Receptor Antagonists Based on 4(5)-ButylimidazoleGeorge Agelis 1 , Amalia Resvani 1 , Tereza Tůmová 2 , Jiřina Slaninová 2 ,and John Matsoukas 31 Department of Chemistry, University of Patras, Patras, 26500, Greece; 2 Institute ofOrganic Chemistry and Biochemistry, AS CR, Prague 6, 16610, Czech Republic;3 ELDRUG S.A., Patras Science Park, Rio, 26504, GreeceIntroductionThe Renin-Angiotensin System (RAS) is known to play an important role in blood pressureregulation and electrolyte homeostasis. Angiotensin II (Ang II), the biologically activepeptide of the RAS, is a potent vasoconstrictor agent which also stimulates aldosteronesecretion and is therefore regarded as a major mediator of hypertensive disorders. Thediscovery of the first orally active Ang II antagonist, losartan, by DuPont [1], opened a newphase of research for the development of other antagonists [2-4]. Nearly all of them containan alkyl-substituted imidazole ring linked to a biphenylmethyltetrazole moiety.Furthermore, the necessity of a ring cluster and of an acidic function ortho substituted tothe distal phenyl ring have been demonstrated for high binding affinity [5,6]. Additionally,the presence of hydroxymethyl group enhances biological activity as well as a bulkylipophilic, electron-withdrawing substitutent, such as a halogen atom seems to favoractivity. In this study, we present an efficient synthesis of imidazole biphenyltetrazolederivatives with reversion of butyl and hydroxymethyl groups at the 2- and 5-positions ofthe imidazole ring in comparison to losartan as potent AT1 Ang II receptor antagonists.Results and DiscussionThis research has focused on the synthesis of analogues that differ in the substitutionpattern around the imidazole ring compared to losartan (Figure 1). In particular, we haveelaborated an efficient synthesis of AT1 Ang II receptor antagonists based on4(5)-butylimidazole in which the hydroxymethyl andbutyl groups attached to the imidazole ring presentdifferent topographical positions in comparison tolosartan [7-9]. The synthesis was regioselective, facileand high yielding, rendering it an efficient process. Thepreparation of the target compounds 20 and 24-26 wasaccomplished starting from the synthesis of thealkylating agent 7 (Figure 2).Fig. 1. Synthesized analoguesbased on 4(5)-butylimidazole.Fig. 2. Synthetic routes for the alkylating agent 7 and the target compounds 20, 24-26.246