Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model

In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30 mpk BID for 2.5 days.

Graphical abstractIn this letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Aβ by 28% and 32% in the cortex and CSF, respectively, in the wild type preclinical Hartley guinea pig animal model when dosed orally at 30 mpk BID for 2.5 days.Figure optionsDownload full-size imageDownload as PowerPoint slide