Design, synthesis and biological evaluation of cyclic angiotensin II analogues with 3,5 side-Chain bridges: Role of C-Terminal aromatic residue and ring cluster for activity and implications in the drug design of AT1 non-peptide antagonists

Abstract

The novel amide linked Angiotensin II (ANG II) cyclic analogues: γ,ε-cyclo(3, 5)-[Sar 1-Glu 3-Lys 5-Ile 8] ANG II (I) and γ, ε-cyclo(3, 5)-[Sar 1-Glu 3-Lys 5-Phe 8] ANG II (II) have been designed, synthesized and bioassayed in anesthetized rabbits in order to unravel structural ring cluster characteristics important for receptor activation. Analogue I with Ile at position 8 was an inhibitor of Angiotensin II while analogue II with Phe at position 8 was found to be an agonist. Similar results were reported for cyclic compounds that have reversed the linking between positions 3 and 5. The overall results show that positions 3 and 5 do not govern the biological activity of the synthetic analogues. It also appears that the aromatic ring cluster (Tyr-His-Phe) in agonist peptides is an essential stereo-electronic feature for Angiotensin II to exert its biological activity. A non-peptide mimetic of ANG II, 1-[2′-[( N-benzyl)tetrazol-5-yl]biphenyl-4-yl]methyl]-2-hydroxymethylbenzimidazole (BZI8) has been designed and synthesized. This molecule is more rigid and much less active than AT 1 non-peptide mimetic losartan probably because it lacks to mimic the orientation of tetrazole and the pharmacophore segments of butyl chain and imidazole ring.