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Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors
Journal article   Open access   Peer reviewed

Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors

Michael A Brodney, Elizabeth M Beck, Christopher R Butler, Gabriela Barreiro, Eric F Johnson, David Riddell, Kevin Parris, Charles E Nolan, Ying Fan, Kevin Atchison, …
Journal of medicinal chemistry, Vol.58(7), pp.3223-3252
04/09/2015
DOI: 10.1021/acs.jmedchem.5b00191
PMCID: PMC4415909
PMID: 25781223
url
https://doi.org/10.1021/acs.jmedchem.5b00191View
Published (Version of record) Open Access

Abstract

In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer’s disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5 . Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug–drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6 , which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.

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