Optimization of a natural product-based class of gamma;-secretase modulators

Jed L. Hubbs, Nathan O. Fuller, Wesley F. Austin, Ruichao Shen, Steffen P. Creaser, Timothy D. McKee, Robyn M.B. Loureiro, Barbara Tate, Weiming Xia, Jeffrey Ives, Brian S. Bronk

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

A series of triterpene-based gamma;-secretase modulators is optimized. An acetate present at the C24 position of the natural product was replaced with either carbamates or ethers to provide compounds with better metabolic stability. With one of those pharmacophores in place at C24, morpholines or carbamates were installed at the C3 position to refine the physicochemical properties of the analogues. This strategy gave compounds with low clearance and good distribution into the central nervous system (CNS) of CD-1 mice. Two of these compounds, 100 and 120, were tested for a pharmacodynamic effect in the strain and lowered brain Aβ42 levels.

Original languageEnglish (US)
Pages (from-to)9270-9282
Number of pages13
JournalJournal of Medicinal Chemistry
Volume55
Issue number21
DOIs
StatePublished - Nov 8 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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