Disulfide Cyclized Tripeptide Analogues of Angiotensin IV as Potent and Selective Inhibitors of Insulin-Regulated Aminopeptidase (IRAP)

The insulin-regulated aminopeptidase (I RAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val(-1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) binds with high affinity to IRA P and inhibits this aminopeptidase (K-i; = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and is believed to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His(4)-Pro(5)-Phe(6) with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent I RAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. Configurational analysis of three pairs of diastercomeric Ang IV analogues was performed using a combination of solution NMR spectroscopic methods, Monte Carlo conformational searches, and NAMFIS calculations. The compounds encompassing L-amino acids only (4, 8, and 12) showed significantly higher bioactivity compared to their up-epimers (5, 9, and 13). The best inhibitors in the series, compounds 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a beta(3)-homotyrosine residue (beta(3)hTyr) replacing Tyr(2), exhibit K-i; values of 3.3 and 5.2 nM, respectively.