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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, 2010From Peptides to Non Peptide Mimetics: The Examples ofAngiotensin II and MyelinAmalia Resvani 1 , George Agelis 1 , Maria-Eleni Androutsou 1 ,Dimitra Kalavrizioti 2 , Konstantinos Kelaidonis 1 , Maria Katsara 3 ,George Deraos 1 , Irene Friligou 1 , Panagiotis Plotas 2 ,Vasso Apostolopoulou 3 , and John Matsoukas 2,41 Department of Chemistry, University of Patras, Patras, 26500, Greece; 2 Department ofMedicine, University of Patras, Patras, 26500, Greece; 3 Immunology and VaccineLaboratory, Austin Campus, Victoria, 3084, Australia; 4 ELDRUG S.A.Patras Science Park, Rio, 26504, GreeceIntroductionIn our laboratory in Patras, research is focused mainly towards design and synthesis of AT1receptor antagonists for treating hypertension as well as of Myelin epitope linear and cyclicanalogues in the immunotherapy of Multiple Sclerosis. Losartan was the first non peptideAngiotensin II (Ang II) receptor antagonist, by Dupont [1] followed by a series of otherAng II antagonists now on the market. Previous Ang II peptide antagonists such asSarilesin and Saralasin [2,3] failed to become drugs due to their peptide nature renderingthem susceptible to proteolytic enzymes. Reversion of butyl and hydroxymethyl groups atthe 2- and 5-positions of the imidazole ring in Losartan resulted in potent AT1 Ang IIreceptor antagonist [4,5].On the other hand, Immunodominant Epitopes MBP 83-99, PLP 139-151, MOG 35-55of human proteins MBP, PLP, MOG [6] of myelin sheath are implicated in MultipleSclerosis (MS). These epitopes have been the tools in our laboratories for the Design,Synthesis and Preclinical Evaluation of linear and cyclic analogues conjugated to reducedor oxidized mannan via [Lys-Gly] bridge. In the light of these results in our research, themain immunodominant peptides MOG 35-55, PLP 139-151 and MBP 83-99 and their headto tail cyclic counterparts alone or conjugated to reduced mannan have been selected toconstitute a mixture cocktail drug for preclinical investigation in preparation of New DrugApplication (NDA) for Clinical Phase I and II studies in the Immunotherapy of MultipleSclerosis.Results and DiscussionResearch work on AT1 receptor antagonists: This research has focused on the design andsynthesis of the analogue 5-butyl-2-hydroxymethyl-1-[[2΄-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole (V8) that differs in the substitution pattern around the imidazole ringcompared to Losartan [4] (Figure 1). Thus, thealkyl chain and hydroxymethyl group possessdifferent topographical position in an attemptto optimize the mimicry of lipophilicsuperimposition of the butyl chain withisopropyl group of Ile5 in Ang II and to probethe significance of the position ofhydroxymethyl group. A general alkylationFig. 1. Synthesized analogue V8 andLosartan.protocol has been developed in this researchwhich facilitates the synthesis of a 1,5disubstituted imidazole derivative by selectivealkylation of N-3 nitrogen of 4(5)-butylimidazolewith biphenyl tetrazole moiety where the N-1 nitrogen is temporarily protectedby the trityl group.In vitro antihypertensive activity of V8 showed similar affinity for the AT 1 receptor,indicating that the reorientation of butyl and hydroxymethyl groups on the imidazoletemplate of losartan retained high binding to the AT 1 receptor. The docking studies areconfirmed by binding assay results which clearly show comparable binding score of thedesigned compound V8 to Losartan.244