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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]

PMID: 18180160

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