Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Aß Reduction.
ACS Med Chem Lett
; 3(11): 897-902, 2012 Nov 08.
Article
in En
| MEDLINE
| ID: mdl-23412139
ABSTRACT
Inhibition of BACE1 to prevent brain Aß peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aß levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aß40 levels when administered orally to rats.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
ACS Med Chem Lett
Year:
2012
Document type:
Article
Affiliation country:
United States