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
  • 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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