Proceedings book download - 5Z.com

Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Synthesis and Biological Evaluation of 1-BiphenylmethylSubstituted Imidazole AT1 ANG II Receptor AntagonistsKonstantinos Kelaidonis 1,4 , George Agelis 1,4 , Dimitra Kalavrizioti 2,4 ,Amalia Resvani 1,4 , John Mikroyiannidis 1 , Panagiotis Plotas 2,4 ,Dimitrios Vlahakos 3 , and John Matsoukas 1,41 Department of Chemistry, University of Patras, Patras, 26 500, Greece; 2 Department ofMedicine, University of Patras, Patras, 26 500, Greece; 3 Department of InternalMedicine, “ΑΤΤΙΚΟΝ” University Hospital, Athens; 4 ELDRUG S.A., PatrasScience Park, Patras, GreeceIntroductionAngiotensin II (ANG II) is the octapeptide produced by the Renin-Angiotensin System(RAS) which plays a central role in blood pressure regulation and electrolyte homeostasis.Inactivation of RAS has stimulated many researchers to design drugs either by inhibitingRenin or the ACE or by blocking the ANG II receptors. The DuPont group was the first todevelop Losartan (DuP 753) [1], an orally effective Angiotensin receptor blocker, which ismetabolized in vivo to the more potent full antagonist EXP 3174 [2]. On the base ofStructure-Activity Relationships (SAR) of the Losartan type AT1 antagonists we report anefficient synthesis of 1-biphenylmethyl substituted AT1 ANG II receptor antagonists basedon Urocanic acid [3].Results and DiscussionWe report herein on the preparation of E-urocanic acid based analogues, focusing ourattention on the structural modifications on the imidazole ring which would possiblyenhance potency. Consequently, we have designed and synthesized a series of urocanicacid derivatives bearing a biphenylmethyl tetrazoleHONONOOOONNNNHFig. 1. Olmesartan Medoxomil,the prodrug of the carboxylicacid Olmesartan, a potent AT1ANG II Receptor Antagonist.moiety at 1-position and a bulky lipophilic and electronwithdrawinggroup such as bromide or iodide, at5-position of the imidazole ring. Thus, the acrylic acidof E-urocanic acid at 4-position can align with theC-terminal carboxyl group of ANG II. Additionally, therigid acrylic or saturated acid side chain was lengthenedby esterification, resulting in the methyl ester or thebulky ester group (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl of Olmesartan Medoxomil [4] (Figure 1),which is in vivo metabolized to the carboxyl moiety andmay provide an effective structural element, emerging tocompounds with improved activity. In vitro biologicalevaluation of the target compounds showed moderatebinding affinity to the AT1 receptor.This work has been the result of SAR and NMR studies on Angiotensin towardsnon-peptide mimetics as drugs for treating hypertension and cardiovascular diseases [5-10].Biphenyl tetrazole derivative 4 was prepared as shown in Figure 2. In Figure 3demonstrates the synthesis of the biphenyl tetrazole derivatives. Urocanic acid 5 wasconverted Fig.1. Small to picture the corresponding inside text. methyl ester 6 by esterification in dry methanol (MeOH).Alkylation No color graphics of the methyl please! ester 6 at the N-1 position of the imidazole ring with the biphenylFig. 2. Reagents and Conditions. (i) Sn(n-Bu) 3 Cl, NaN 3 , Tol; (ii) HCl in THF/H 2 O, thenClt-Cl, TEA, DCM; (iii) NBS, DBP, CCl 4 , reflux.248