Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors

This letter describes replacements for the P3 amide moiety present in previously reported tertiary carbinamine macrolactones. Although P-gp efflux issues associated with these amide-macrolactones were solved and full brain penetration was measured in one case, potency was compromised in the process.

Graphical abstractThis letter describes replacements for the P3 amide moiety present in previously reported tertiary carbinamine macrolactones. Although P-gp efflux issues associated with these amide-macrolactones were solved and brain penetration was measured in one case, potency was compromised in the process.Figure optionsDownload full-size imageDownload as PowerPoint slide