Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors

  • Bioorg Med Chem Lett. 2018 Jul 1;28(12):2195-2200. doi: 10.1016/j.bmcl.2018.05.003.
Siem Jakob Veenstra  1 ,  Heinrich Rueeger  1 ,  Markus Voegtle  1 ,  Rainer Lueoend  1 ,  Philipp Holzer  1 ,  Konstanze Hurth  1 ,  Marina Tintelnot-Blomley  1 ,  Mathias Frederiksen  1 ,  Jean-Michel Rondeau  2 ,  Laura Jacobson  3 ,  Matthias Staufenbiel  3 ,  Ulf Neumann  3 ,  Rainer Machauer  4
Affiliations
  • 1. Department of Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4057 Basel, Switzerland.
  • 2. Center for Proteomic Chemistry, Structural Biology Platform, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4057 Basel, Switzerland.
  • 3. Department of Neuroscience, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4057 Basel, Switzerland.
  • 4. Department of Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4057 Basel, Switzerland. Electronic address: [email protected].
PMID: 29764741 DOI: 10.1016/j.bmcl.2018.05.003
Abstract

New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Aβ levels in mice in an acute treatment regimen.

Keywords
Alzheimer’s disease; Amino-1,4-oxazines; BACE-1; P-gp; pK(a).
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