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An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities.

Yuan Cheng1, James Brown1, Ted C Judd1

  • 1Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.

ACS Medicinal Chemistry Letters
|February 21, 2015
PubMed
Summary
This summary is machine-generated.

Researchers developed a novel BACE1 inhibitor, compound 15, which effectively lowers amyloid-beta (Aβ) peptide levels in the brain and cerebrospinal fluid (CSF). This orally available drug candidate shows promise for Alzheimer's disease treatment with a good safety profile.

Keywords:
Alzheimer’s disease (AD)Aβaminooxazolinexantheneβ-site amyloid precursor protein cleaving enzyme 1 (BACE1)

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Drug Discovery

Background:

  • Alzheimer's disease (AD) poses a significant challenge, with amyloid-beta (Aβ) peptide accumulation being a key pathological hallmark.
  • Beta-secretase 1 (BACE1) inhibition is a promising therapeutic strategy to reduce Aβ production and modify disease progression.

Purpose of the Study:

  • To optimize aminooxazoline xanthene derivatives as potent BACE1 inhibitors.
  • To identify an orally available BACE1 inhibitor with robust efficacy and a favorable safety profile for potential Alzheimer's disease treatment.

Main Methods:

  • Structure- and property-based drug design approach.
  • Optimization of lead compounds to discover novel BACE1 inhibitors.
  • In vivo studies in rats and nonhuman primates to assess Aβ reduction.
  • In vitro assays for hERG channel activity and cardiovascular safety assessment.

Main Results:

  • Discovery of compound 15, a highly efficacious orally available BACE1 inhibitor.
  • Compound 15 significantly reduced cerebrospinal fluid (CSF) and brain Aβ levels in preclinical models.
  • Compound 15 demonstrated low activity against the hERG ion channel.
  • Favorable tolerability observed in an integrated cardiovascular safety model.

Conclusions:

  • Compound 15 represents a promising drug candidate for Alzheimer's disease, effectively targeting Aβ production.
  • The optimized inhibitor exhibits a strong efficacy and safety profile, warranting further clinical investigation.
  • BACE1 inhibition remains a viable therapeutic avenue for disease-modifying Alzheimer's treatments.