2. Academic Validation
  3. Optimization of 1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors Toward a Clinical Candidate

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

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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