Identification and characterization of a new cognitive enhancer based on inhibition of insulin-regulated aminopeptidase
Anthony L Albiston, Craig J Morton, Hooi Ling Ng, Vi Pham, Holly R Yeatman, Siying Ye, Ruani N Fernando, Dimitri De Bundel, David B Ascher, Frederick AO Mendelsohn, Michael W Parker, Siew Yeen Chai
FASEB JOURNAL | WILEY | Published : 2008
Approximately one-quarter of people over the age of 65 are estimated to suffer some form of cognitive impairment, underscoring the need for effective cognitive-enhancing agents. Insulin-regulated aminopeptidase (IRAP) is potentially an innovative target for the development of cognitive enhancers, as its peptide inhibitors exhibit memory-enhancing effects in both normal and memory-impaired rodents. Using a homology model of the catalytic domain of IRAP and virtual screening, we have identified a class of nonpeptide, small-molecule inhibitors of IRAP. Structure-based computational development of an initial "hit" resulted in the identification of two divergent families of compounds. Subsequent ..View full abstract
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Awarded by National Health and Medical Research Council of Australia (NHMRC)
This work was supported by grants from the National Health and Medical Research Council of Australia (NHMRC development grants 454714 and 520695), Neurosciences Victoria, and Alzheimer's Drug Discovery Foundation/ Institute for the Study of Aging, USA. D.D.B. is a Scientific Research Fellow of the Research Foundation, Flanders, Belgium. D.B.A is an Australian Postgraduate Award Scholar and a recipient of a St. Vincent's Institute Foundation Scholarship sponsored by Colin North and Major Engineering. M.W.P. is an Australian Research Council Federation Fellow and an NHMRC Honorary Fellow. S.Y.C. is an NHMRC Senior Research Fellow. The authors acknowledge the contribution of Dr. Keith Watson in the design of the analogues of HFI-142, Prof. William Charman for the solubility and blood brain barrier permeability studies, and Mr. Tom Vale for assistance with the animal surgery.