دورية أكاديمية
From fragment screening to in vivo efficacy: optimization of a series of 2-aminoquinolines as potent inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1).
| العنوان: | From fragment screening to in vivo efficacy: optimization of a series of 2-aminoquinolines as potent inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). |
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| المؤلفون: | Cheng Y; Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. yuanc@amgen.com, Judd TC, Bartberger MD, Brown J, Chen K, Fremeau RT Jr, Hickman D, Hitchcock SA, Jordan B, Li V, Lopez P, Louie SW, Luo Y, Michelsen K, Nixey T, Powers TS, Rattan C, Sickmier EA, St Jean DJ Jr, Wahl RC, Wen PH, Wood S |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2011 Aug 25; Vol. 54 (16), pp. 5836-57. Date of Electronic Publication: 2011 Jul 29. |
| نوع المنشور: | Journal Article; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Aminoquinolines/*chemical synthesis , Aminoquinolines/*pharmacology , Amyloid Precursor Protein Secretases/*antagonists & inhibitors , Aspartic Acid Endopeptidases/*antagonists & inhibitors, Aminoquinolines/chemistry ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Peptides/cerebrospinal fluid ; Animals ; Aspartic Acid Endopeptidases/metabolism ; Biocatalysis/drug effects ; Brain/drug effects ; Brain/metabolism ; Catalytic Domain ; Cell Line ; Crystallography, X-Ray ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; HEK293 Cells ; Humans ; Male ; Models, Chemical ; Models, Molecular ; Molecular Structure ; Protein Structure, Tertiary ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship |
| مستخلص: | Using fragment-based screening of a focused fragment library, 2-aminoquinoline 1 was identified as an initial hit for BACE1. Further SAR development was supported by X-ray structures of BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery of potent compounds. These strategies enabled us to integrate the C-3 side chain on 2-aminoquinoline 1 extending deep into the P2' binding pocket of BACE1 and enhancing the ligand's potency. We were able to improve the BACE1 potency to subnanomolar range, over 10(6)-fold more potent than the initial hit (900 μM). Further elaboration of the physical properties of the lead compounds to those more consistent with good blood-brain barrier permeability led to inhibitors with greatly improved cellular activity and permeability. Compound 59 showed an IC(50) value of 11 nM on BACE1 and cellular activity of 80 nM. This compound was advanced into rat pharmacokinetic and pharmacodynamic studies and demonstrated significant reduction of Aβ levels in cerebrospinal fluid (CSF). (© 2011 American Chemical Society) |
| سلسلة جزيئية: | PDB 3RSV; 3RSX; 3RTH; 3RTM; 3RTN; 3RU1; 3RVI |
| المشرفين على المادة: | 0 (Aminoquinolines) 0 (Amyloid beta-Peptides) 0 (Enzyme Inhibitors) EC 3.4.- (Amyloid Precursor Protein Secretases) EC 3.4.23.- (Aspartic Acid Endopeptidases) EC 3.4.23.46 (BACE1 protein, human) |
| تواريخ الأحداث: | Date Created: 20110629 Date Completed: 20111209 Latest Revision: 20110818 |
| رمز التحديث: | 20240829 |
| DOI: | 10.1021/jm200544q |
| PMID: | 21707077 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/jm200544q |