开发2-氨基恶唑啉3-氮杂呫吨类化合物作为口服有效的β-分泌酶抑制剂用于阿尔茨海默病的潜在治疗。
Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer's disease.
作者信息
Chen Jian Jeffrey, Liu Qingyian, Yuan Chester, Gore Vijay, Lopez Patricia, Ma Vu, Amegadzie Albert, Qian Wenyuan, Judd Ted C, Minatti Ana E, Brown James, Cheng Yuan, Xue May, Zhong Wenge, Dineen Thomas A, Epstein Oleg, Human Jason, Kreiman Charles, Marx Isaac, Weiss Matthew M, Hitchcock Stephen A, Powers Timothy S, Chen Kui, Wen Paul H, Whittington Douglas A, Cheng Alan C, Bartberger Michael D, Hickman Dean, Werner Jonathan A, Vargas Hugo M, Everds Nancy E, Vonderfecht Steven L, Dunn Robert T, Wood Stephen, Fremeau Robert T, White Ryan D, Patel Vinod F
机构信息
Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
出版信息
Bioorg Med Chem Lett. 2015 Feb 15;25(4):767-74. doi: 10.1016/j.bmcl.2014.12.092. Epub 2015 Jan 8.
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.
β-位点淀粉样前体蛋白（APP）裂解酶1（BACE1）是治疗阿尔茨海默病最热门的靶点之一。我们采用基于结构和性质的药物设计方法，确定2-氨基恶唑啉3-氮杂呫吨为有效的BACE1抑制剂，其在大鼠药效学模型中显著降低了脑脊液和脑内Aβ水平。与最初的先导化合物2相比，化合物28在非人类灵长类动物心血管安全性模型中表现出较低的QTc延长潜力。
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