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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Vydané v:	Journal of medicinal chemistry Ročník 57; číslo 4; s. 1368 - 1377
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	WASHINGTON Amer Chemical Soc 27.02.2014
Predmet:	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
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804 1520-4804
DOI:	10.1021/jm401540f