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

Bioorg. Med. Chem. Lett., 2009, 19(15), 4427-4431, doi:10.1016/j.bmcl.2009.05.053 published on 01.08.2009
Bioorganic & Medicinal Chemistry Letters, online article
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 47 nM) and the corresponding linear analog I were tested for serum stability. The approach led to three times prolonged half life serum stability of 44 min for the macrocyclic inhibitor II-P1 compared to the linear compound I.

TU München
Helmholtz München
MPI of Neurobiology
MPI of Biochemistry