Optimization of 1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors Toward a Clinical Candidate

  • J Med Chem. 2018 Jun 28;61(12):5292-5303. doi: 10.1021/acs.jmedchem.8b00304.
Harrie J M Gijsen  1 ,  Sergio A Alonso de Diego  2 ,  Michel De Cleyn  1 ,  Aránzazu García-Molina  2 ,  Gregor J Macdonald  1 ,  Carolina Martínez-Lamenca  1 ,  Daniel Oehlrich  1 ,  Hana Prokopcova  1 ,  Frederik J R Rombouts  1 ,  Michel Surkyn  1 ,  Andrés A Trabanco  2 ,  Sven Van Brandt  1 ,  Dries Van den Bossche  1 ,  Michiel Van Gool  2 ,  Nigel Austin  3 ,  Herman Borghys  3 ,  Deborah Dhuyvetter  3 ,  Diederik Moechars  4
Affiliations
  • 1. Neuroscience Medicinal Chemistry, Janssen Research & Development , Janssen Pharmaceutica NV , Turnhoutseweg 30 , B-2340 Beerse , Belgium.
  • 2. Neuroscience Medicinal Chemistry, Janssen Research & Development , Janssen-Cilag SA , C/Jarama 75A , 45007 Toledo , Spain.
  • 3. Discovery Sciences, Janssen Research & Development , Janssen Pharmaceutica NV , Turnhoutseweg 30 , B-2340 Beerse , Belgium.
  • 4. Neuroscience Biology, Janssen Research & Development , Janssen Pharmaceutica NV , Turnhoutseweg 30 , B-2340 Beerse , Belgium.
PMID: 29809004 DOI: 10.1021/acs.jmedchem.8b00304
Abstract

In previous studies, the introduction of electron withdrawing groups to 1,4-oxazine BACE1 inhibitors reduced the p Ka of the amidine group, resulting in compound 2 that showed excellent in vivo efficacy, lowering Aβ levels in brain and CSF. However, a suboptimal cardiovascular safety margin, based on QTc prolongation, prevented further progression. Further optimization resulted in the replacement of the 2-fluoro substituent by a CF3-group, which reduced hERG inhibition. This has led to compound 3, with an improved cardiovascular safety margin and sufficiently safe in GLP toxicity studies to progress into clinical trials.

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