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Crystal structure of BACE1 in complex with 2-aminooxazoline 3-azaxanthene inhibitor 28Crystal structure of BACE1 in complex with 2-aminooxazoline 3-azaxanthene inhibitor 28
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 PubMedThe beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Abeta levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model. Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious beta-secretase inhibitors for the potential treatment of Alzheimer's disease.,Chen JJ, Liu Q, Yuan C, Gore V, Lopez P, Ma V, Amegadzie A, Qian W, Judd TC, Minatti AE, Brown J, Cheng Y, Xue M, Zhong W, Dineen TA, Epstein O, Human J, Kreiman C, Marx I, Weiss MM, Hitchcock SA, Powers TS, Chen K, Wen PH, Whittington DA, Cheng AC, Bartberger MD, Hickman D, Werner JA, Vargas HM, Everds NE, Vonderfecht SL, Dunn RT 2nd, Wood S, Fremeau RT Jr, White RD, Patel VF Bioorg Med Chem Lett. 2015 Feb 15;25(4):767-74. doi: 10.1016/j.bmcl.2014.12.092. , Epub 2015 Jan 8. PMID:25613679[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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