Evaluation of a Series of β‑Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads
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 ner...
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| Veröffentlicht in: | ACS medicinal chemistry letters 2019-08, Vol.10 (8), p.1159-1165 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1021/acsmedchemlett.9b00181 |
| format | Article |
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| fulltext | fulltext |
| identifier | ISSN: 1948-5875 |
| ispartof | ACS medicinal chemistry letters, 2019-08, Vol.10 (8), p.1159-1165 |
| issn | 1948-5875 1948-5875 |
| language | eng |
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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; ACS Publications; PubMed Central |
| subjects | Letter |
| title | Evaluation of a Series of β‑Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads |
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