Evaluation of a Series of β‑Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads

• Published in: ACS medicinal chemistry letters Vol. 10; no. 8; pp. 1159 - 1165
• Main Authors: Oehlrich, Daniel, Peschiulli, Aldo, Tresadern, Gary, Van Gool, Michiel, Vega, Juan Antonio, De Lucas, Ana Isabel, Alonso de Diego, Sergio A, Prokopcova, Hana, Austin, Nigel, Van Brandt, Sven, Surkyn, Michel, De Cleyn, Michel, Vos, Ann, Rombouts, Frederik J. R, Macdonald, Gregor, Moechars, Dieder, Gijsen, Harrie J. M, Trabanco, Andrés A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08.08.2019
• Subjects: Letter; pK a; BACE inhibitor; Alzheimer’s disease; cyclic sulfamidates; β-secretase 1
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.9b00181

Despite several years of research, only a handful of β-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer’s disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC50 ≤ 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.