کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1397313 | 1501137 | 2014 | 10 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis](/preview/png/1397313.png)
• Dual site modulators of insulin-degrading-enzyme were discovered by screening.
• X-ray structure of co-crystals and preliminary structure–activity relationships are described.
• Selective inhibition of amyloid-beta degradation over insulin hydrolysis was possible.
• Neuroblastoma cells treated with compounds display a dose-dependent increase in amyloid-beta levels.
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.
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Journal: European Journal of Medicinal Chemistry - Volume 79, 22 May 2014, Pages 184–193