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

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

  • Bioorg Med Chem Lett. 2008 Feb 1;18(3):1031-6. doi: 10.1016/j.bmcl.2007.12.028.
Arun K Ghosh 1,  Nagaswamy Kumaragurubaran,  Lin Hong,  Sarang Kulkarni,  Xiaoming Xu,  Heather B Miller,  Dandepally Srinivasa Reddy,  Vajira Weerasena,  Robert Turner,  Wanpin Chang,  Gerald Koelsch,  Jordan Tang
Affiliations

Affiliation

  • 1 Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA. akghosh@purdue.edu
PMID: 18180160 DOI: 10.1016/j.bmcl.2007.12.028
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.

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