4XXS: Crystal Structure Of Bace1 With A Pyrazole-substituted Tetrahydropyran Thioamidine

In recent years, the first generation of beta-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.
PDB ID: 4XXSDownload
MMDB ID: 128275
PDB Deposition Date: 2015/1/30
Updated in MMDB: 2015/04
Experimental Method:
x-ray diffraction
Resolution: 1.86  Å
Source Organism:
Similar Structures:
Biological Unit for 4XXS: monomeric; determined by author and by software (PISA)
Molecular Components in 4XXS
Label Count Molecule
Protein (1 molecule)
Beta-secretase 1(Gene symbol: BACE1)
Molecule annotation
Chemicals (8 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB