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长大医专

上传于：2015-12-29

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我是大学的一名学生，学的是医学专业，我会整理医学类儿科资料

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    188宝金博页面版: Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzh

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    内容提示： Development of 2-aminooxazoline 3-azaxanthenes as orallyefficacious b-secretase inhibitors for the potential treatmentof Alzheimer’s diseaseJian Jeffrey Chena, ? , Qingyian Liu a , Chester Yuan a , Vijay Gore a , Patricia Lopez a , Vu Ma a ,Albert Amegadziea , Wenyuan Qian a , Ted C. Judd a , Ana E. Minatti a , James Brown a , Yuan Cheng a ,May Xuea , Wenge Zhong a , Thomas A. Dineen g , Oleg Epstein g , Jason Human g , Charles Kreiman g ,Isaac Marxg , Matthew M. Weiss g , Stephen A. Hitchcock a , Timoth...

    文档格式：PDF | 页数：11 | 浏览次数：451 | 上传日期：2015-12-29 23:27:16 | 文档星级：
    Development of 2-aminooxazoline 3-azaxanthenes as orallyefficacious b-secretase inhibitors for the potential treatmentof Alzheimer’s diseaseJian Jeffrey Chena, ⇑ , Qingyian Liu a , Chester Yuan a , Vijay Gore a , Patricia Lopez a , Vu Ma a ,Albert Amegadziea , Wenyuan Qian a , Ted C. Judd a , Ana E. Minatti a , James Brown a , Yuan Cheng a ,May Xuea , Wenge Zhong a , Thomas A. Dineen g , Oleg Epstein g , Jason Human g , Charles Kreiman g ,Isaac Marxg , Matthew M. Weiss g , Stephen A. Hitchcock a , Timothy S. Powers a , Kui Chen e , Paul H. Wen c ,Douglas A. Whittingtonh , Alan C. Cheng h , Michael D. Bartberger b , Dean Hickman d , Jonathan A. Werner f ,Hugo M. Vargasf , Nancy E. Everds f , Steven L. Vonderfecht f , Robert T. Dunn II f , Stephen Wood c ,Robert T. Fremeau Jr.c , Ryan D. White g , Vinod F. Patel ga Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USAb Department of Molecular Structure, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USAc Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USAd Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USAe Department of HTS and Molecular Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USAf Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USAg Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USAh Department of Molecular Structure, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USAa r t i c l e i n f oArticle history:Received 12 November 2014Revised 23 December 2014Accepted 29 December 2014Available online 8 January 2015Keywords:Alzheimer’s disease (AD)b-Secretase (BACE1)AminooxazolineXanthene3-AzaxantheneAmyloidAb peptidesa b s t r a c tThe b-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursuedtargets for the treatment of Alzheimer’s disease. We used a structure- and property-based drug designapproach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantlyreduced CSF and brain Ab levels in a rat pharmacodynamic model. Compared to the initial lead 2, com-pound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascularsafety model.? 2015 Elsevier Ltd. All rights reserved.Alzheimer’s disease (AD) is characterized by progressive loss ofcognitive ability, dementia, and eventually death. It is the sixthleading cause of death in the United States and currently there isno cure for the disease. The direct cost to care for AD patients in2013 was estimated to be 220 billion dollars in the United Statesalone. 1Studies over the last decade have suggested that one of themain causes of the disease is the accumulation, oligomerization,and aggregation of amyloid-b peptides (Ab). 2,3 One of the mostwidely explored disease modifying approaches has focused onreducing the accumulation of these Ab peptides. 4 Discovered in1999, the b-site amyloid precursor protein cleaving enzyme 1(BACE1) is an aspartic protease comprised of 501 amino acids, 5and is the rate-limiting enzyme for the formation of Ab peptides. 6Inhibitors of BACE1 represent a potential disease-modifying treat-ment of AD. 7,8Early generation BACE1 inhibitors were substrate or transition-state analogs containing a number of amide bonds to maintainhydrogen bonding interactions with the enzyme. 8 These peptidom-imetic compounds suffered from poor pharmacokinetics (PK) andcentral nervous system (CNS) permeability due to high polarhttp://dx.doi.org/10.1016/j.bmcl.2014.12.0920960-894X/? 2015 Elsevier Ltd. All rights reserved.⇑ Corresponding author. Tel.: +1 805 447 8498; fax: +1 805 480 1337E-mail address: jianc@amgen.com (J.J. Chen).Bioorganic & Medicinal Chemistry Letters 25 (2015) 767–774Contents lists available at ScienceDirectBioorganic & Medicinal Chemistry Lettersjournal homepage: www.elsevier.com/locate/bmcl

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