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Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-? hydrolysis.

ABSTRACT: 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.

SUBMITTER: Charton J 

PROVIDER: S-EPMC4128174 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis.

Charton Julie J   Gauriot Marion M   Guo Qing Q   Hennuyer Nathalie N   Marechal Xavier X   Dumont Julie J   Hamdane Malika M   Pottiez Virginie V   Landry Valerie V   Sperandio Olivier O   Flipo Marion M   Buee Luc L   Staels Bart B   Leroux Florence F   Tang Wei-Jen WJ   Deprez Benoit B   Deprez-Poulain Rebecca R  

European journal of medicinal chemistry 20140404

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 st  ...[more]

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