Spirocyclic 尾-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: From Hit to Lowering of Cerebrospinal Fluid (CSF) Amyloid 尾 in a Higher Species
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- 作者：Kevin W. Hunt ; Adam W. Cook ; Ryan J. Watts ; Christopher T. Clark ; Guy Vigers ; Darin Smith ; Andrew T. Metcalf ; Indrani W. Gunawardana ; Michael Burkard ; April A. Cox ; Mary K. Geck Do ; Darrin Dutcher ; Allen A. Thomas ; Sumeet Rana ; Nicholas C. Kallan ; Robert K. DeLisle ; James P. Rizzi ; Kelly Regal ; Douglas Sammond ; Robert Groneberg ; Michael Siu ; Hans Purkey ; Joseph P. Lyssikatos ; Allison Marlow ; Xingrong Liu ; Tony P. Tang
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：April 25, 2013
- 年：2013
- 卷：56
- 期：8
- 页码：3379-3403
- 全文大小：776K
- 年卷期：v.56,no.8(April 25, 2013)
- ISSN：1520-4804
文摘
A hallmark of Alzheimer鈥檚 disease is the brain deposition of amyloid beta (A尾), a peptide of 36鈥?3 amino acids that is likely a primary driver of neurodegeneration. A尾 is produced by the sequential cleavage of APP by BACE1 and 纬-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer鈥檚 disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF A尾 in vivo, despite efflux. Starting with spirocycle 1a, we explore structure鈥揳ctivity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood鈥揵rain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF A尾 lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF A尾 in rodents and in monkey.