Diastereoselective synthesis of fused cyclopropyl-3-amino-2,4-oxazine β-amyloid cleaving enzyme (BACE) inhibitors and their biological evaluation

Jonathan D Low; Michael D Bartberger; Yuan Cheng; Doug Whittington; Quifen Xue; Stephen Wood; Jennifer R Allen; Ana E Minatti

doi:10.1016/j.bmcl.2018.01.056

Diastereoselective synthesis of fused cyclopropyl-3-amino-2,4-oxazine β-amyloid cleaving enzyme (BACE) inhibitors and their biological evaluation

Bioorg Med Chem Lett. 2018 Apr 1;28(6):1111-1115. doi: 10.1016/j.bmcl.2018.01.056. Epub 2018 Feb 1.

Authors

Jonathan D Low¹, Michael D Bartberger², Yuan Cheng³, Doug Whittington⁴, Quifen Xue³, Stephen Wood⁵, Jennifer R Allen³, Ana E Minatti⁶

Affiliations

¹ Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. Electronic address: low@amgen.com.
² Department of Molecular Engineering, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
³ Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
⁴ Department of Molecular Engineering, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
⁵ Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
⁶ Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. Electronic address: aminatti@amgen.com.

PMID: 29426770
DOI: 10.1016/j.bmcl.2018.01.056

Abstract

The diastereoselective synthesis and structure activity relationship (SAR) of a series of fused cyclopropyl-3-amino-2,4-oxazine (2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine)-containing BACE inhibitors is described. Through these efforts compound 2 was identified as a potent (cell IC₅₀ = 15 nM) BACE inhibitor with acceptable ADME properties. When tested in vivo, compound 2 demonstrated a significant reduction of brain and cerebral spinal fluid (CSF) Aβ₄₀ levels (46% and 66%, respectively) in a rat pharmacodynamic study and thus represents a suitable starting point for the further development of in vivo efficacious compounds for the treatment of Alzheimer's disease.

Keywords: Alzheimer’s disease (AD); BACE inhibitor; Oxazine; Structure-based design; β-Secretase.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Animals
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / metabolism
Aza Compounds / chemical synthesis
Aza Compounds / chemistry
Aza Compounds / pharmacology*
Bridged Bicyclo Compounds / chemical synthesis
Bridged Bicyclo Compounds / chemistry
Bridged Bicyclo Compounds / pharmacology*
Crystallography, X-Ray
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Models, Molecular
Molecular Structure
Rats
Rats, Sprague-Dawley
Stereoisomerism
Structure-Activity Relationship

Substances

Aza Compounds
Bridged Bicyclo Compounds
Enzyme Inhibitors
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human