Comparison of three gamma-turn mimetic scaffolds incorporated into angiotensin II

Rigidification of peptides by cyclization and iterative incorporation of we ll-defined secondary structure mimetics constitutes one approach to the des ign of non-peptidergic structures with better defined conformations. We her ein present the synthesis of a potential gamma-turn mimetic scaffold, and i ts incorporation in the 3-5 position of angiotensin II. Two analogues of an giotensin TI (Ang II) incorporating this 1,3,5-trisubstituted benzene gamma -turn scaffold were synthesized. Evaluation of the compounds in a radioliga nd binding assay showed that they lacked affinity to the AT(1) receptor. To rationalize these results a geometrical and electrostatical comparison wit h Ang II analogues encompassing a bicyclic scaffold that delivered inactive pseudo peptides and an azepine scaffold producing highly active ligands wa s made. This analysis did not provide a clear rationale for the inactivity of the benzene gamma-turn scaffolds. (C) 2000 Elsevier Science Ltd. All rig hts reserved.