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

ABSTRACT: 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.

SUBMITTER: Peschiulli A

PROVIDER: S-EPMC8762732 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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

Peschiulli Aldo A Oehlrich Daniel D Van Gool Michiel M Austin Nigel N Van Brandt Sven S Surkyn Michel M De Cleyn Michel M Vos Ann A Tresadern Gary G Rombouts Frederik J R FJR Macdonald Gregor J GJ Moechars Diederik D Trabanco Andrés A AA Gijsen Harrie J M HJM

ACS medicinal chemistry letters 20211201 1

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 <b>36</b>, a highly potent (hAβ42 cell IC<sub>50</sub> = 1.3 nM), cardiovascularly ...[more]

PMID: 35059126

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