5clm | pdb_00005clm

1,4-Oxazine BACE1 inhibitors

spinqualitylabelsall models 5clm, resolution 2.61Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5clm is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 52K, CL, IOD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BACE1_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. Publication Abstract from PubMed 1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa whilst optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active and which demonstrated robust lowering of Abeta levels in vivo in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE inhibitors for the treatment of Alzheimer's Disease. 1,4-Oxazine beta-secretase (BACE1) inhibitors: from hit generation to orally bioavailable brain penetrant leads.,Rombouts FJ, Tresadern G, Delgado O, Martinez Lamenca C, Van Gool M, Garcia-Molina A, Alonso De Diego SA, Oehlrich D, Prokopcova H, Alonso JM, Austin N, Borghys H, Van Brandt S, Surkyn M, De Cleyn M, Vos A, Alexander R, Macdonald GJ, Moechars D, Gijsen HJ, Trabanco AA J Med Chem. 2015 Sep 17. PMID:26378740 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase 3D structures

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