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

Bioorganic & Medicinal Chemistry Letters
Arun K GhoshJordan Tang

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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Citations

Feb 16, 2010·Aging Clinical and Experimental Research·Francesco PanzaAlberto Pilotto
Nov 10, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Wan-Pin ChangJordan Tang
Dec 24, 2011·Acta Crystallographica. Section D, Biological Crystallography·Yechun XuJoel L Sussman
May 1, 2009·Expert Review of Neurotherapeutics·Taisuke Tomita
Apr 1, 2009·Expert Opinion on Drug Discovery·Yoshio Hamada, Yoshiaki Kiso
Apr 10, 2013·Expert Opinion on Drug Discovery·Yoshio Hamada, Yoshiaki Kiso
Mar 9, 2011·Analytical Biochemistry·Tony ChristopeitU Helena Danielson
May 18, 2010·Journal of Peptide Science : an Official Publication of the European Peptide Society·Taeko KakizawaYoshiaki Kiso
Mar 23, 2013·Biochimica Et Biophysica Acta·Kathleen CoughlanJordan Tang
Apr 15, 2017·Journal of Chemical Information and Modeling·Shilva KayasthaAlexandre Varnek
Sep 4, 2009·Journal of Cellular and Molecular Medicine·Rossen DonevJohannes Thome
Jul 28, 2011·Medicinal Research Reviews·Rafael LeónJosé Marco-Contelles
Apr 3, 2014·Chemical Society Reviews·Arun K Ghosh, Heather L Osswald
Nov 30, 2011·Journal of Neurochemistry·Arun K GhoshJordan Tang
Jan 11, 2019·Medicinal Research Reviews·Nalini SchaduangratChanin Nantasenamat
Jul 28, 2019·Medicinal Research Reviews·Nour M Moussa-PachaTaleb H Al-Tel
Aug 29, 2012·Clinica Chimica Acta; International Journal of Clinical Chemistry·M SathyaM Anusuyadevi
Nov 18, 2008·Journal of Medicinal Chemistry·Scott C MayerJ Steven Jacobsen

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