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

  • J Med Chem. 2015 Apr 9;58(7):3223-52. doi: 10.1021/acs.jmedchem.5b00191.
Michael A Brodney ,  Elizabeth M Beck ,  Christopher R Butler ,  Gabriela Barreiro ,  Eric F Johnson  1 ,  David Riddell ,  Kevin Parris ,  Charles E Nolan ,  Ying Fan  1 ,  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  2 ,  Yong Zhang  2 ,  Brian T O'Neill
Affiliations
  • 1. #The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92024, United States.
  • 2. ∇WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
PMID: 25781223 DOI: 10.1021/acs.jmedchem.5b00191
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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