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A Brain-Penetrant and Bioavailable Pyrazolopiperazine BACE1 Inhibitor Elicits Sustained Reduction of Amyloid β In Vivo

We recently disclosed a set of heteroaryl-fused piperazine inhibitors of BACE1 that combined nanomolar potency with good intrinsic permeability and low Pgp-mediated efflux. Herein we describe further work on two prototypes of this family of inhibitors aimed at modulating their basicity and reducing...

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Published in:ACS medicinal chemistry letters 2022-01, Vol.13 (1), p.76-83
Main Authors: Peschiulli, Aldo, Oehlrich, Daniel, Van Gool, Michiel, Austin, Nigel, Van Brandt, Sven, Surkyn, Michel, De Cleyn, Michel, Vos, Ann, Tresadern, Gary, Rombouts, Frederik J. R, Macdonald, Gregor J, Moechars, Diederik, Trabanco, Andrés A, Gijsen, Harrie J. M
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Language:English
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Summary:We recently disclosed a set of heteroaryl-fused piperazine inhibitors of BACE1 that combined nanomolar potency with good intrinsic permeability and low Pgp-mediated efflux. Herein we describe further work on two prototypes of this family of inhibitors aimed at modulating their basicity and reducing binding to the human ether-a-go-go-related gene (hERG) channel. This effort has led to the identification of compound 36, a highly potent (hAβ42 cell IC50 = 1.3 nM), cardiovascularly safe, and orally bioavailable compound that elicited sustained Aβ42 reduction in mouse and dog animal models.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.1c00445