1333228-00-4Relevant articles and documents
Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis
Charton, Julie,Gauriot, Marion,Guo, Qing,Hennuyer, Nathalie,Marechal, Xavier,Dumont, Julie,Hamdane, Malika,Pottiez, Virginie,Landry, Valerie,Sperandio, Olivier,Flipo, Marion,Buee, Luc,Staels, Bart,Leroux, Florence,Tang, Wei-Jen,Deprez, Benoit,Deprez-Poulain, Rebecca
, p. 184 - 193 (2014)
Insulin degrading enzyme (IDE) is a highly conserved zinc metalloprotease that is involved in the clearance of various physiologically peptides like amyloid-beta and insulin. This enzyme has been involved in the physiopathology of diabetes and Alzheimer's disease. We describe here a series of small molecules discovered by screening. Co-crystallization of the compounds with IDE revealed a binding both at the permanent exosite and at the discontinuous, conformational catalytic site. Preliminary structure-activity relationships are described. Selective inhibition of amyloid-beta degradation over insulin hydrolysis was possible. Neuroblastoma cells treated with the optimized compound display a dose-dependent increase in amyloid-beta levels.
