Download MendeleyDiastereoselective synthesis of fused cyclopropyl-3-amino-2,4-oxazine beta-amyloid cleaving enzyme (BACE) inhibitors and their biological evaluation.
Low, J.D., Bartberger, M.D., Cheng, Y., Whittington, D., Xue, Q., Wood, S., Allen, J.R., Minatti, A.E.(2018) Bioorg Med Chem Lett 28: 1111-1115
- PubMed: 29426770
- DOI: https://doi.org/10.1016/j.bmcl.2018.01.056
- Primary Citation of Related Structures:
6C2I - PubMed 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 IC 50 = 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) Aβ 40 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.
Organizational Affiliation:
Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. Electronic address: low@amgen.com.
