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Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors |
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| Authors: | Siem Jakob Veenstra Heinrich Rueeger Markus Voegtle Rainer Lueoend Philipp Holzer Konstanze Hurth Marina Tintelnot-Blomley Mathias Frederiksen Jean-Michel Rondeau Laura Jacobson Matthias Staufenbiel Ulf Neumann Rainer Machauer |
| Institution: | 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 |
| 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 BACE-1 Amino-1 4-oxazines P-gp |
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