4j0v
From Proteopedia
CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH 5-Cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide
Structural highlights
FunctionBACE1_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.[1] [2] Publication Abstract from PubMedAn extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Abeta40 & 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Abeta40 & 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo. beta-Secretase (BACE1) Inhibitors with High In Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer's Disease.,Hilpert H, Guba W, Woltering TJ, Wostl W, Pinard E, Mauser H, Mayweg AV, Rogers-Evans M, Humm R, Krummenacher D, Muser T, Schnider C, Jacobsen H, Ozmen L, Bergadano A, Banner DW, Hochstrasser R, Kuglstatter A, David-Pierson P, Fischer H, Polara A, Narquizian R J Med Chem. 2013 Apr 16. PMID:23590342[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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