Optimization of a Natural Product-Based Class of γ-Secretase Modulators
Journal of Medicinal Chemistry2012Vol. 55(21), pp. 9270–9282
Citations Over TimeTop 10% of 2012 papers
Jed L. Hubbs, Nathan O. Fuller, Wesley Austin, Ruichao Shen, Steffen P. Creaser, Timothy D. McKee, Robyn Loureiro, Barbara Tate, Weiming Xia, Jeffrey L. Ives, Brian S. Bronk
Abstract
A series of triterpene-based γ-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.
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