Referenced in: none

Automatically associated channels: Kv11.1

Title: Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors.

Authors: 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, Cathleen Gonzales, Ashley E Robshaw, Shawn D Doran, Mark W Bundesmann, Leanne Buzon, Jason Dutra, Kevin Henegar, Erik LaChapelle, Xinjun Hou, Bruce N Rogers, Jayvardhan Pandit, Ricardo Lira, Luis Martinez-Alsina, Peter Mikochik, John C Murray, Kevin Ogilvie, Loren Price, Subas M Sakya, Aijia Yu, Yong Zhang, Brian T O'Neill

Journal, date & volume: J. Med. Chem., 2015 Apr 9 , 58, 3223-52

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25781223

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.