Literature DB >> 22390835

Structure based design of iminohydantoin BACE1 inhibitors: identification of an orally available, centrally active BACE1 inhibitor.

Jared N Cumming1, Elizabeth M Smith, Lingyan Wang, Jeffrey Misiaszek, James Durkin, Jianping Pan, Ulrich Iserloh, Yusheng Wu, Zhaoning Zhu, Corey Strickland, Johannes Voigt, Xia Chen, Matthew E Kennedy, Reshma Kuvelkar, Lynn A Hyde, Kathleen Cox, Leonard Favreau, Michael F Czarniecki, William J Greenlee, Brian A McKittrick, Eric M Parker, Andrew W Stamford.   

Abstract

From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aβ following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.
Copyright © 2012 Elsevier Ltd. All rights reserved.

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Year:  2012        PMID： 22390835     DOI： 10.1016/j.bmcl.2012.02.013

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


  27 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

4.  Evaluation of aminohydantoins as a novel class of antimalarial agents.

Authors:  Marvin J Meyers; Micky D Tortorella; Jing Xu; Limei Qin; Zhengxiang He; Xingfen Lang; Wentian Zeng; Wanwan Xu; Li Qin; Michael J Prinsen; Francis M Sverdrup; Christopher S Eickhoff; David W Griggs; Jonathan Oliva; Peter G Ruminski; E Jon Jacobsen; Mary A Campbell; David C Wood; Daniel E Goldberg; Xiaorong Liu; Yongzhi Lu; Xin Lu; Zhengchao Tu; Xiaoyun Lu; Ke Ding; Xiaoping Chen
Journal:  ACS Med Chem Lett       Date:  2013-12-06       Impact factor: 4.345

5.  CNS amyloid-β, soluble APP-α and -β kinetics during BACE inhibition.

Authors:  Justyna A Dobrowolska; Maria S Michener; Guoxin Wu; Bruce W Patterson; Robert Chott; Vitaliy Ovod; Yuriy Pyatkivskyy; Kristin R Wildsmith; Tom Kasten; Parker Mathers; Mandy Dancho; Christina Lennox; Brad E Smith; David Gilberto; Debra McLoughlin; Daniel J Holder; Andrew W Stamford; Kevin E Yarasheski; Matthew E Kennedy; Mary J Savage; Randall J Bateman
Journal:  J Neurosci       Date:  2014-06-11       Impact factor: 6.167

6.  Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease.

Authors:  Fredrik Jeppsson; Susanna Eketjäll; Juliette Janson; Sofia Karlström; Susanne Gustavsson; Lise-Lotte Olsson; Ann-Cathrine Radesäter; Bart Ploeger; Gvido Cebers; Karin Kolmodin; Britt-Marie Swahn; Stefan von Berg; Tjerk Bueters; Johanna Fälting
Journal:  J Biol Chem       Date:  2012-10-09       Impact factor: 5.157

7.  Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance.

Authors:  Zhiyuan Zhu; Jianming Yan; Wei Jiang; Xin-gang Yao; Jing Chen; Lili Chen; Chenjing Li; Lihong Hu; Hualiang Jiang; Xu Shen
Journal:  J Neurosci       Date:  2013-08-07       Impact factor: 6.167

8.  Development of 2-aminooxazoline 3-azaxanthene β-amyloid cleaving enzyme (BACE) inhibitors with improved selectivity against Cathepsin D.

Authors:  Jonathan D Low; Michael D Bartberger; Kui Chen; Yuan Cheng; Mark R Fielden; Vijay Gore; Dean Hickman; Qingyian Liu; E Allen Sickmier; Hugo M Vargas; Jonathan Werner; Ryan D White; Douglas A Whittington; Stephen Wood; Ana E Minatti
Journal:  Medchemcomm       Date:  2017-04-27       Impact factor: 3.597

Review 9.  Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects.

Authors:  Robert Vassar; Peer-Hendrik Kuhn; Christian Haass; Matthew E Kennedy; Lawrence Rajendran; Philip C Wong; Stefan F Lichtenthaler
Journal:  J Neurochem       Date:  2014-04-19       Impact factor: 5.372

10.  Large scale relative protein ligand binding affinities using non-equilibrium alchemy.

Authors:  Vytautas Gapsys; Laura Pérez-Benito; Matteo Aldeghi; Daniel Seeliger; Herman van Vlijmen; Gary Tresadern; Bert L de Groot
Journal:  Chem Sci       Date:  2019-12-02       Impact factor: 9.825
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