Prolonged stability by cyclization: Macrocyclic phosphino dipeptide isostere inhibitors of β-secretase (BACE1)

The design, synthesis and activity of a macrocyclic phosphino dipeptide isostere inhibitor of BACE1 with improved human serum stability are reported. Cyclization of recently reported linear phosphino dipeptide isostere inhibitors of BACE1 via side chain olefin metathesis yielded macrocyclic BACE1 inhibitors. The most potent compound II-P1 (IC50 of 47nM) and the corresponding linear analog I were tested for serum stability. The approach led to three times prolonged half life serum stability of 44min for the macrocyclic inhibitor II-P1 compared to the linear compound I.