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Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: From hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species
Authors
Michael Burkard
Christopher T. Clark
+24 more
Adam W. Cook
April A. Cox
Robert K. Delisle
Darrin Dutcher
Mary K. Geck Do
Robert Groneberg
Indrani W. Gunawardana
Kevin W. Hunt
Nicholas C. Kallan
Xingrong Liu
Joseph P. Lyssikatos
Allison Marlow
Andrew T. Metcalf
Hans Purkey
Sumeet Rana
Kelly Regal
James P. Rizzi
Douglas Sammond
Michael Siu
Darin Smith
Tony P. Tang
Allen A. Thomas
Guy Vigers
Ryan J. Watts
Publication date
25 April 2013
Publisher
ePublications at Regis University
Abstract
A hallmark of Alzheimer\u27s disease is the brain deposition of amyloid beta (Aβ), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer\u27s disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain 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 Aβ lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey. © 2013 American Chemical Society
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Last time updated on 13/01/2021