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

doi:10.1021/jm300976b

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 journal › Article › peer-review

41 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 language	English (US)
Pages (from-to)	9270-9282
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	21
DOIs	https://doi.org/10.1021/jm300976b
State	Published - Nov 8 2012

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/jm300976b

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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.",

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AU - Hubbs, Jed L.

AU - Fuller, Nathan O.

AU - Austin, Wesley F.

AU - Shen, Ruichao

AU - Creaser, Steffen P.

AU - McKee, Timothy D.

AU - Loureiro, Robyn M.B.

AU - Tate, Barbara

AU - Xia, Weiming

AU - Ives, Jeffrey

AU - Bronk, Brian S.

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

Abstract

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