2. Academic Validation
  3. Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors

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

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: rainer.machauer@novartis.com.
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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