Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer's disease.
Basic Information
ID: ALA3393054
Journal: Bioorg Med Chem Lett
Title: Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer's disease.
Authors: 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, Wood S, Fremeau RT, White RD, Patel VF.
Abstract: The β-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 Aβ 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.
CiteXplore: 25613679
DOI: 10.1016/j.bmcl.2014.12.092
Patent ID: ┄