Spirocyclic Sulfamides as 尾-Secretase 1 (BACE-1) Inhibitors for the Treatment of Alzheimer鈥檚 Disease: Utilization of Structure Based Drug Design, WaterMap, and CNS Penetration Studies To Identify Cent

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• 作者：Michael A. Brodney ; Gabriela Barreiro ; Kevin Ogilvie ; Eva Hajos-Korcsok ; John Murray ; Felix Vajdos ; Claude Ambroise ; Curt Christoffersen ; Katherine Fisher ; Lorraine Lanyon ; JianHua Liu ; Charles E. Nolan ; Jane M. Withka ; Kris A. Borzilleri ; Ivan Efremov ; Christine E. Oborski ; Alison Varghese ; Brian T. O鈥橬eill
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：55
• 期：21
• 页码：9224-9239
• 全文大小：662K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

尾-Secretase 1 (BACE-1) is an attractive therapeutic target for the treatment and prevention of Alzheimer鈥檚 disease (AD). Herein, we describe the discovery of a novel class of BACE-1 inhibitors represented by sulfamide 14g, using a medicinal chemistry strategy to optimize central nervous system (CNS) penetration by minimizing hydrogen bond donors (HBDs) and reducing P-glycoprotein (P-gp) mediated efflux. We have also taken advantage of the combination of structure based drug design (SBDD) to guide the optimization of the sulfamide analogues and the in silico tool WaterMap to explain the observed SAR. Compound 14g is a potent inhibitor of BACE-1 with excellent permeability and a moderate P-gp liability. Administration of 14g to mice produced a significant, dose-dependent reduction in central A尾_X-40 levels at a free drug exposure equivalent to the whole cell IC₅₀ (100 nM). Furthermore, studies of the P-gp knockout mouse provided evidence that efflux transporters affected the amount of A尾 lowering versus that observed in wild-type (WT) mouse at an equivalent dose.