Generation of Leads for γ-Secretase Modulation

J Med Chem. 2020 Aug 13;63(15):8216-8230. doi: 10.1021/acs.jmedchem.0c00446. Epub 2020 Aug 4.

Abstract

Herein, we disclose three structurally differentiated γ-secretase modulators (GSMs) based on an oxadiazine scaffold. The analogues from series I potently inhibit the generation of Aβ42 in vitro when the substituents at 3 and 4 positions of the oxadiazine moiety adopt an α orientation (cf. 11). To address the concern around potential reactivity of the exocyclic double bond present in series I toward nucleophilic attack, compounds containing either an endocyclic double bond, such as 20 (series II), or devoid of an olefinic moiety, such as 27 (series III), were designed and validated as novel GSMs. Compound 11 and azepine 20 exhibit robust lowering of CSF Aβ42 in rats treated with a 30 mg/kg oral dose.

MeSH terms

  • Alkenes / chemistry
  • Alkenes / pharmacology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Animals
  • Binding Sites / physiology
  • HEK293 Cells
  • Humans
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / cerebrospinal fluid
  • Rats
  • Structure-Activity Relationship

Substances

  • Alkenes
  • Amyloid beta-Peptides
  • Oxadiazoles
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases