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

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

  • ACS Med Chem Lett. 2021 Dec 1;13(1):76-83. doi: 10.1021/acsmedchemlett.1c00445.
Aldo Peschiulli 1,  Daniel Oehlrich 1,  Michiel Van Gool 2,  Nigel Austin 1,  Sven Van Brandt 1,  Michel Surkyn 1,  Michel De Cleyn 1,  Ann Vos 1,  Gary Tresadern 1,  Frederik J R Rombouts 1,  Gregor J Macdonald 1,  Diederik Moechars 1,  Andrés A Trabanco 2,  Harrie J M Gijsen 1
Affiliations

Affiliations

  • 1 Discovery Chemistry, Discovery Sciences, DMPK, Discovery Sciences, and Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • 2 Discovery Chemistry, Discovery Sciences, Janssen Research & Development, Janssen-Cilag S.A., C/Jarama 75A, 45007 Toledo, Spain.
PMID: 35059126 DOI: 10.1021/acsmedchemlett.1c00445
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.

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