Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP).
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, Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) 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 His(4)-Pro(5)-Phe(6) 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 β(3)-homotyrosine residue (β(3)hTyr) replacing Tyr(2), exhibit K(i) values of 3.3 and 5.2 nM, respectively.
Department of Medicinal Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
Hanna
H
Andersson
Heidi
H
Demaegdt
Georges
G
Vauquelin
Gunnar
G
Lindeberg
Anders
A
Karlén
Mathias
M
Hallberg
Máté
M
Erdélyi
Anders
A
Hallberg
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D010122:Cystinyl Aminopeptidase / Q000037:antagonists & inhibitors*; D004220:Disulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009010:Monte Carlo Method; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004220:Disulfides; D009842:Oligopeptides; D010456:Peptides, Cyclic; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase