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. Epub 2015 Apr 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry*
  • Amyloidogenic Proteins / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry*
  • Crystallography, X-Ray
  • Cytochrome P-450 CYP2D6 / chemistry*
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism
  • Drug Design
  • Drug Interactions*
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Mice, Inbred Strains
  • Models, Molecular
  • Molecular Sequence Data
  • Protease Inhibitors / administration & dosage
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology*
  • Pyrazoles / chemistry
  • Structure-Activity Relationship

Substances

  • Amyloidogenic Proteins
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • Protease Inhibitors
  • Pyrazoles
  • pyrazole
  • Cytochrome P-450 CYP2D6
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human

Associated data

  • PDB/4XRY
  • PDB/4XRZ
  • PDB/4XXS