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Potent memapsin 2 (beta-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation.


ABSTRACT: Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic beta-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (K(i) 1.8 nM) and cellular (IC(50)=1 nM in Chinese hamster ovary cells) assays. Inhibitor 24 has also shown very impressive in vivo properties (up to 65% reduction of plasma A beta) in transgenic mice. The X-ray structure of protein-ligand complex of memapsin 2 revealed critical interactions in the memapsin 2 active site.

SUBMITTER: Ghosh AK 

PROVIDER: S-EPMC2577816 | biostudies-other | 2008 Feb

REPOSITORIES: biostudies-other

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Potent memapsin 2 (beta-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation.

Ghosh Arun K AK   Kumaragurubaran Nagaswamy N   Hong Lin L   Kulkarni Sarang S   Xu Xiaoming X   Miller Heather B HB   Reddy Dandepally Srinivasa DS   Weerasena Vajira V   Turner Robert R   Chang Wanpin W   Koelsch Gerald G   Tang Jordan J  

Bioorganic & medicinal chemistry letters 20080103 3


Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic beta-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (K(i) 1.8 nM) and cellular (IC(50)=1 nM in Chinese hamster ovary cells) assays. Inhibitor 24 has also shown very impressive in vivo properties (up to 65% reduction of plasma A beta) in transgenic mice. The X-ray struct  ...[more]

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