Open AccessDiscovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS Aβ Reduction
Author(s) -
Andrew W. Stamford,
Jack D. Scott,
Sarah W. Li,
Suresh Babu,
Dawit Tadesse,
Rachael C. Hunter,
Yusheng Wu,
Jeffrey Misiaszek,
Jared N. Cumming,
Eric J. Gilbert,
Chunli Huang,
Brian A. McKittrick,
Liwu Hong,
Tao Guo,
Zhiwei Zhu,
Corey Strickland,
Peter Orth,
Johannes Voigt,
Matthew Kennedy,
Xia Chen,
Reshma Kuvelkar,
Robert A. Hodgson,
Lynn A. Hyde,
Kathleen Cox,
Leonard Favreau,
Eric M. Parker,
William J. Greenlee
Publication year - 2012
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml3001165
Subject(s) - penetrant (biochemical) , pharmacology , drug discovery , medicine , neuroscience , chemistry , biology , biochemistry , organic chemistry
Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats.