Synthesis, Structure-Activity Relationships and Brain Uptake of a Novel Series of Benzopyran Inhibitors of Insulin-Regulated Aminopeptidase

Peptide inhibitors of insulin-regulated aminopeptidase (IRAP) enhance fear avoidance and spatial memory and accelerate spatial learning in a number of memory paradigms. Using a virtual screening approach, a series of benzopyran compounds was identified that inhibited the catalytic activity of IRAP,...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 57; no. 4; pp. 1368 - 1377
Main Authors: Mountford, Simon J., Albiston, Anthony L., Charman, William N., Ng, Leelee, Holien, Jessica K., Parker, Michael W., Nicolazzo, Joseph A., Thompson, Philip E., Chai, Siew Yeen
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 27.02.2014
Subjects:
Aminopeptidases - antagonists & inhibitors
Animals
Benzopyrans - chemical synthesis
Benzopyrans - chemistry
Benzopyrans - pharmacokinetics
Benzopyrans - pharmacology
Brain - metabolism
Cell Line
Chemistry, Medicinal
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Humans
Insulin - pharmacology
Life Sciences & Biomedicine
Magnetic Resonance Spectroscopy
Pharmacology & Pharmacy
Rats
Science & Technology
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
WATER MAZE
POTENT
(IRAP)/AT RECEPTOR
LIGANDS
LVV-HEMORPHIN-7
ANGIOTENSIN-IV
ATTENUATION
RATS
SPATIAL MEMORY DEFICITS
PASSIVE-AVOIDANCE
ISSN:0022-2623, 1520-4804, 1520-4804
Online Access:Get more information
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Summary:Peptide inhibitors of insulin-regulated aminopeptidase (IRAP) enhance fear avoidance and spatial memory and accelerate spatial learning in a number of memory paradigms. Using a virtual screening approach, a series of benzopyran compounds was identified that inhibited the catalytic activity of IRAP, ultimately resulting in the identification of potent and specific inhibitors. The present study describes the medicinal chemistry campaign that led to the development of the lead candidate, 3, highlighting the key structural features considered as critical for binding. Furthermore, the in vivo pharmacokinetics and brain uptake of compounds (1 and 3) were assessed in rats and were complemented with in vitro human and rat microsomal stability studies. Following intravenous administration to rodents, 3 exhibits brain exposure, albeit it is rapidly converted to 1, a compound which also exhibits potent inhibition of IRAP.
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ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/jm401540f