4RRO: 8-tetrahydropyran-2-yl Chromans: Highly Selective Beta-site Amyloid Precursor Protein Cleaving Enzyme 1 (bace1) Inhibitors

A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Abeta1-40 at 60 mg/kg (PO).
PDB ID: 4RRODownload
MMDB ID: 125249
PDB Deposition Date: 2014/11/6
Updated in MMDB: 2014/12
Experimental Method:
x-ray diffraction
Resolution: 1.8  Å
Source Organism:
Similar Structures:
Biological Unit for 4RRO: monomeric; determined by author and by software (PISA)
Molecular Components in 4RRO
Label Count Molecule
Protein (1 molecule)
Beta-secretase 1(Gene symbol: BACE1)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB