Design, synthesis, and SAR of macrocyclic tertiary carbinamine BACE-1 inhibitors

This Letter describes the design and synthesis of tertiary carbinamine macrocyclic inhibitors of the β-secretase (BACE-1) enzyme. These macrocyclic inhibitors, some of which incorporate novel P2 substituents, display a 2- to 100-fold increase in potency relative to the previously described acyclic analogs while affording greater stability.

Graphical abstractThis Letter describes the design and synthesis of tertiary carbinamine macrocyclic inhibitors of the β-secretase (BACE-1) enzyme. These macrocyclic inhibitors, some of which incorporate novel P2 substituents, display a 2- to 100-fold increase in potency relative to the previously described acyclic analogs while affording greater stability.Figure optionsDownload full-size imageDownload as PowerPoint slide