Inhibitors of β-site amyloid precursor protein cleaving enzyme (BACE1): identification of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718)

  • J Med Chem. 2014 Dec 11;57(23):9811-31. doi: 10.1021/jm5012676.
Thomas A Dineen  1 ,  Kui Chen ,  Alan C Cheng ,  Katayoun Derakhchan ,  Oleg Epstein ,  Joel Esmay ,  Dean Hickman ,  Chuck E Kreiman ,  Isaac E Marx ,  Robert C Wahl ,  Paul H Wen ,  Matthew M Weiss ,  Douglas A Whittington ,  Stephen Wood ,  Robert T Fremeau Jr ,  Ryan D White ,  Vinod F Patel
Affiliations
  • 1. Departments of Therapeutic Discovery, ‡Neuroscience, §Molecular Structure and Characterization, ∥Pharmacokinetics and Drug Metabolism, and ⊥Comparative Biology and Safety Sciences, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
PMID: 25363711 DOI: 10.1021/jm5012676
Abstract

We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain Aβ levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.

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