5HDX: Bace-1 In Complex With (7ar)-7a-(5-cyanothiophen-2-yl)-6-(4-ethoxy-5- Fluoro-6-methylpyrimidin-2-yl)-3-methyl-4-oxooctahydro-2h-pyrrolo[3, 4-d]pyrimidin-2-iminium

We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2'-S2'' pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Abeta40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Abeta in nonrodent preclinical species.
PDB ID: 5HDXDownload
MMDB ID: 137540
PDB Deposition Date: 2016/1/5
Updated in MMDB: 2016/06
Experimental Method:
x-ray diffraction
Resolution: 1.6  Å
Source Organism:
Similar Structures:
Biological Unit for 5HDX: monomeric; determined by author and by software (PISA)
Molecular Components in 5HDX
Label Count Molecule
Protein (1 molecule)
Beta-secretase 1(Gene symbol: BACE1)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB