Literature DB >> 21388807

Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors.

Heinrich Rueeger1, Jean-Michel Rondeau, Clive McCarthy, Henrik Möbitz, Marina Tintelnot-Blomley, Ulf Neumann, Sandrine Desrayaud.   

Abstract

This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described.
Copyright © 2011 Elsevier Ltd. All rights reserved.

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Year:  2011        PMID： 21388807     DOI： 10.1016/j.bmcl.2011.02.038

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  11 in total

1.  Alzheimer's Disease is Driven by Intraneuronally Retained Beta-Amyloid Produced in the AD-Specific, βAPP-Independent Pathway: Current Perspective and Experimental Models for Tomorrow.

Authors:  Vladimir Volloch; Bjorn Olsen; Sophia Rits
Journal:  Ann Integr Mol Med       Date:  2020

2.  Precursor-Independent Overproduction of Beta-Amyloid in AD: Mitochondrial Dysfunction as Possible Initiator of Asymmetric RNA-Dependent βAPP mRNA Amplification. An Engine that Drives Alzheimer's Disease.

Authors:  Vladimir Volloch; Bjorn R Olsen; Sophia Rits
Journal:  Ann Integr Mol Med       Date:  2019-11-20

3.  Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Aβ Reduction.

Authors:  Andrew W Stamford; Jack D Scott; Sarah W Li; Suresh Babu; Dawit Tadesse; Rachael Hunter; Yusheng Wu; Jeffrey Misiaszek; Jared N Cumming; Eric J Gilbert; Chunli Huang; Brian A McKittrick; Liwu Hong; Tao Guo; Zhaoning Zhu; Corey Strickland; Peter Orth; Johannes H Voigt; Matthew E Kennedy; Xia Chen; Reshma Kuvelkar; Robert Hodgson; Lynn A Hyde; Kathleen Cox; Leonard Favreau; Eric M Parker; William J Greenlee
Journal:  ACS Med Chem Lett       Date:  2012-07-12       Impact factor: 4.345

Review 4.  The β-secretase (BACE) inhibitor NB-360 in preclinical models: From amyloid-β reduction to downstream disease-relevant effects.

Authors:  Ulf Neumann; Rainer Machauer; Derya R Shimshek
Journal:  Br J Pharmacol       Date:  2019-03-10       Impact factor: 8.739

Review 5.  The structural evolution of β-secretase inhibitors: a focus on the development of small-molecule inhibitors.

Authors:  Stefania Butini; Simone Brogi; Ettore Novellino; Giuseppe Campiani; Arun K Ghosh; Margherita Brindisi; Sandra Gemma
Journal:  Curr Top Med Chem       Date:  2013       Impact factor: 3.295

6.  Retrospective molecular docking study of WY-25105 ligand to β-secretase and bias of the three-dimensional structure flexibility.

Authors:  Leo Ghemtio; Nicolas Muzet
Journal:  J Mol Model       Date:  2013-04-07       Impact factor: 1.810

Review 7.  BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease.

Authors:  Arun K Ghosh; Heather L Osswald
Journal:  Chem Soc Rev       Date:  2014-10-07       Impact factor: 54.564

Review 8.  Results of Beta Secretase-Inhibitor Clinical Trials Support Amyloid Precursor Protein-Independent Generation of Beta Amyloid in Sporadic Alzheimer's Disease.

Authors:  Vladimir Volloch; Sophia Rits
Journal:  Med Sci (Basel)       Date:  2018-06-02

9.  The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease.

Authors:  Ulf Neumann; Mike Ufer; Laura H Jacobson; Marie-Laure Rouzade-Dominguez; Gunilla Huledal; Carine Kolly; Rainer M Lüönd; Rainer Machauer; Siem J Veenstra; Konstanze Hurth; Heinrich Rueeger; Marina Tintelnot-Blomley; Matthias Staufenbiel; Derya R Shimshek; Ludovic Perrot; Wilfried Frieauff; Valerie Dubost; Hilmar Schiller; Barbara Vogg; Karen Beltz; Alexandre Avrameas; Sandrine Kretz; Nicole Pezous; Jean-Michel Rondeau; Nicolau Beckmann; Andreas Hartmann; Stefan Vormfelde; Olivier J David; Bruno Galli; Rita Ramos; Ana Graf; Cristina Lopez Lopez
Journal:  EMBO Mol Med       Date:  2018-11       Impact factor: 12.137

10.  Design, Synthesis, and Biological Evaluation of 2-(Benzylamino-2-Hydroxyalkyl)Isoindoline-1,3-Diones Derivatives as Potential Disease-Modifying Multifunctional Anti-Alzheimer Agents.

Authors:  Dawid Panek; Anna Więckowska; Anna Pasieka; Justyna Godyń; Jakub Jończyk; Marek Bajda; Damijan Knez; Stanislav Gobec; Barbara Malawska
Journal:  Molecules       Date:  2018-02-07       Impact factor: 4.411
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