DESIGN OF BACE1 INHIBITERS POSSESSING A MEDIUM-RING STRUCTURE AT THE P3 POSITION

Yoshio Hamada

Faculty of Frontiers of Innovative Research in Science and Technology, Konan University, Hyogo, Japan

Abstract

Β-Secretase (BACE1) is a molecular target for developing anti-Alzheimer’s disease drugs. We recently reported a series of BACE1 inhibitors possessing a 2,6-pyridinedicarboxylic or isophthalic scaffold at the P2 position [1-4]. Although these inhibitors showed potent inhibitory activities (BACE1 IC50 = 9–13 nM), they possess amide bonds that reduce in vivo stability and permeability across the blood brain barrier (BBB). The inherent substrate of BACE1, amyloid precursor protein (APP), has a bulky hydrophobic valine residue in the P3 position. Because our BACE1 inhibitor contains an aromatic ring in the P3 position, we envisioned substituting the P3-aromatic ring with a bulky medium-ring structure. Since the medium ring can sterically protect the P3-amide bond in the inhibitors, it is expected that in vivo stability and membrane/BBB permeability will be improved [1]. Y. Hamada, Y. Kiso, Biopolymers, 2016, 106, 563-579 [2]. Y. Hamada, Y. Kiso, Amino Acids, Peptides and Proteins, Royal Society of Chemistry, London, 2016, 39. 114-147 [3]. Y. Hamada, SOJ Pharmacy & Pharmaceutical Sci., 2014, 1, 1-8 [4]. Y. Hamada, Y. Kiso, Expert Opinion on Drug Discovery, 2013, 8, 709-731.

Keywords: Alzheimer's disease, BACE1 inhibitor.