Functional gamma‐secretase inhibitors reduce beta‐amyloid peptide levels in brainHarry F. Dovey, Varghese John, J. P. Anderson et al.|Journal of Neurochemistry|2001 Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma-secretase inhibitors will enable a clinical examination of the A beta hypothesis that Ass peptide drives the neuropathology observed in Alzheimer's disease.
A new class of angiotensin-converting enzyme inhibitorsDesign, Synthesis, and Crystal Structure of Hydroxyethyl Secondary Amine-Based Peptidomimetic Inhibitors of Human β-SecretaseMichel Maillard, Roy K. Hom, Timothy E. Benson et al.|Journal of Medicinal Chemistry|2007 The design and synthesis of a novel series of potent and cell permeable peptidomimetic inhibitors of the human beta-secretase (BACE) are described. These inhibitors feature a hydroxyethyl secondary amine isostere and a novel aromatic ring replacement for the C-terminus. The crystal structure of BACE in complex with this hydroxyethyl secondary amine isostere inhibitor is also presented.
From Peptide to Non-Peptide. 2. The de Novo Design of Potent, Non-peptidal Inhibitors of Platelet Aggregation Based on a Benzodiazepinedione ScaffoldRobert S. McDowell, Brent Blackburn, Thomas R. Gadek et al.|Journal of the American Chemical Society|1994 ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTFrom Peptide to Non-Peptide. 2. The de Novo Design of Potent, Non-peptidal Inhibitors of Platelet Aggregation Based on a Benzodiazepinedione ScaffoldRobert S. McDowell, Brent K. Blackburn, Thomas R. Gadek, Lawrence R. McGee, Thomas Rawson, Mark E. Reynolds, Kirk D. Robarge, Todd C. Somers, Eugene D. Thorsett, and Cite this: J. Am. Chem. Soc. 1994, 116, 12, 5077–5083Publication Date (Print):June 1, 1994Publication History Published online1 May 2002Published inissue 1 June 1994https://pubs.acs.org/doi/10.1021/ja00091a008https://doi.org/10.1021/ja00091a008research-articleACS PublicationsRequest reuse permissionsArticle Views493Altmetric-Citations97LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts
Conformationally restricted inhibitors of angiotensin-converting enzyme. Synthesis and computationsA series of inhibitors of angiotensin converting enzyme (ACE, dipeptidyl carboxypeptidase, EC 3.4.15.1) is described which addresses certain conformational aspects of the enzyme-inhibitor interaction. In this study the alanylproline portion of the potent ACE inhibitor enalaprilat (2) is replaced by a series of monocyclic lactams containing the required recognition and binding elements. In order to more fully assess the lactam ring conformations and the key backbone angle psi as defined in 3 with respect to possible enzyme-bound conformations, a series of model lactams was investigated with use of molecular mechanics. The results point to a correlation between inhibitor potency (IC50) and the computed psi angle for the lowest energy conformation of the model compounds. Thus the psi angle as defined in 3 is an important determinant in the binding of inhibitors to ACE. The inhibition data in conjunction with the computational data have served to define a window of psi angles from 130 degrees to 170 degrees which seems to be acceptable to the ACE active site.