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

H Andersson, Heidi Demaegdt, Georges Vauquelin, G. Lindeberg, A. Karlen, M. Hallberg, M. Erdélyi, A. Hallberg

Onderzoeksoutput: Articlepeer review

52 Citaten (Scopus)

Samenvatting

The insulin-regulated aminopeptidase (IRAP) 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, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 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 His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. Configurational analysis of three pairs of diastereomeric 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 lld-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 ?3-homotyrosine residue (?3hTyr) replacing Tyr2, exhibit Ki values of 3.3 and 5.2 nM, respectively.
Originele taal-2English
Pagina's (van-tot)8059-8071
Aantal pagina's13
TijdschriftJournal of Medicinal Chemistry
Volume53
Nummer van het tijdschrift22
StatusPublished - 2010

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