A Brain-Penetrant and Bioavailable Pyrazolopiperazine BACE1 Inhibitor Elicits Sustained Reduction of Amyloid β In Vivo.
| Autor: | Peschiulli A; Discovery Chemistry, Discovery Sciences, DMPK, Discovery Sciences, and Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Oehlrich D; Discovery Chemistry, Discovery Sciences, DMPK, Discovery Sciences, and Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Van Gool M; Discovery Chemistry, Discovery Sciences, Janssen Research & Development, Janssen-Cilag S.A., C/Jarama 75A, 45007 Toledo, Spain., Austin N; Discovery Chemistry, Discovery Sciences, DMPK, Discovery Sciences, and Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Van Brandt S; Discovery Chemistry, Discovery Sciences, DMPK, Discovery Sciences, and Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Surkyn M; Discovery Chemistry, Discovery Sciences, DMPK, Discovery Sciences, and Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium., De Cleyn M; Discovery Chemistry, Discovery Sciences, DMPK, Discovery Sciences, and Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Vos A; Discovery Chemistry, Discovery Sciences, DMPK, Discovery Sciences, and Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Tresadern G; Discovery Chemistry, Discovery Sciences, DMPK, Discovery Sciences, and Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Rombouts FJR; Discovery Chemistry, Discovery Sciences, DMPK, Discovery Sciences, and Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Macdonald GJ; Discovery Chemistry, Discovery Sciences, DMPK, Discovery Sciences, and Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Moechars D; Discovery Chemistry, Discovery Sciences, DMPK, Discovery Sciences, and Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Trabanco AA; Discovery Chemistry, Discovery Sciences, Janssen Research & Development, Janssen-Cilag S.A., C/Jarama 75A, 45007 Toledo, Spain., Gijsen HJM; Discovery Chemistry, Discovery Sciences, DMPK, Discovery Sciences, and Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium. |
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| Jazyk: | angličtina |
| Zdroj: | ACS medicinal chemistry letters [ACS Med Chem Lett] 2021 Dec 01; Vol. 13 (1), pp. 76-83. Date of Electronic Publication: 2021 Dec 01 (Print Publication: 2022). |
| DOI: | 10.1021/acsmedchemlett.1c00445 |
| Abstrakt: | 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 IC Competing Interests: The authors declare no competing financial interest. (© 2021 American Chemical Society.) |
| Databáze: | MEDLINE |
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