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

• Published in: Journal of medicinal chemistry Vol. 53; no. 22; pp. 8059 - 8071
• Main Authors: Andersson, Hanna, Demaegdt, Heidi, Vauquelin, Georges, Lindeberg, Gunnar, Karlén, Anders, Hallberg, Mathias, Erdélyi, Máté, Hallberg, Anders
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.11.2010; Amer Chemical Soc
• Subjects: angiotensin; Angiotensin II - analogs & derivatives; Angiotensin II - chemical synthesis; Angiotensin II - chemistry; Angiotensin II - pharmacology; angiotensin IV; Animals; Cell Line; Chemistry; Chemistry, Medicinal; Cricetinae; Cricetulus; Cystinyl Aminopeptidase - antagonists & inhibitors; disulfide; Disulfides - chemical synthesis; Disulfides - chemistry; Disulfides - pharmacology; Fysikalisk kemi; Humans; inhibitor; insulin-regulated aminopeptidase; IRAP; Kemi; Life Sciences & Biomedicine; Läkemedelskemi; Magnetic Resonance Spectroscopy; Medicinal Chemistry; Models, Molecular; Molecular Conformation; Monte Carlo Method; NAMFIS; NATURAL SCIENCES; NATURVETENSKAP; NMR; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Organic Chemistry; Organisk kemi; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; peptidomimetics; Pharmaceutical chemistry; Pharmacology & Pharmacy; Physical Chemistry; Science & Technology; Stereoisomerism; Structure-Activity Relationship; RESIDUAL DIPOLAR COUPLINGS; ACTIVE-SITE; NMR-SPECTROSCOPY; RELATIVE CONFIGURATION; CYSTINYL AMINOPEPTIDASE; AT RECEPTOR-LIGAND; BINDING; PEPTIDE; GENETIC ALGORITHM; CONFORMATIONS
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm100793t

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 (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 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 β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit K i values of 3.3 and 5.2 nM, respectively.