Open AccessEvaluation of a Series of β-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads
Author(s) -
Daniel Oehlrich,
Aldo Peschiulli,
Gary Tresadern,
Michiel Van Gool,
Javier Martínez Vega,
Ana Isabel de Lucas,
Sergio A. Alonso de Diego,
Hana Prokopcová,
Nigel Austin,
Sven Van Brandt,
Michel Surkyn,
Michel De Cleyn,
Ann Vos,
Frederik Rombouts,
Gregor Macdonald,
Dieder Moechars,
Harrie J. M. Gijsen,
Andrés A. Trabanco
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00181
Subject(s) - amidine , chemistry , piperazine , combinatorial chemistry , pharmacology , biochemistry , stereochemistry , medicine , organic chemistry
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 (IC 50 ≤ 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.