Initial optimization of a new series of γ-secretase modulators derived from a triterpene glycoside

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

doi:10.1021/ml300256p

Initial optimization of a new series of γ-secretase modulators derived from a triterpene glycoside

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

Houston Methodist

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

The discovery of a new series of γ-secretase modulators is disclosed. Starting from a triterpene glycoside γ-secretase modulator that gave a very low brain-to-plasma ratio, initial SAR and optimization involved replacement of a pendant sugar with a series of morpholines. This modification led to two compounds with significantly improved central nervous system (CNS) exposure.

Original language	English (US)
Pages (from-to)	908-913
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	3
Issue number	11
DOIs	https://doi.org/10.1021/ml300256p
State	Published - Nov 8 2012

Keywords

γ-secretase
Alzheimer's disease
amyloid β
black cohosh
modulator

ASJC Scopus subject areas

Organic Chemistry
Drug Discovery
Biochemistry

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title = "Initial optimization of a new series of γ-secretase modulators derived from a triterpene glycoside",

abstract = "The discovery of a new series of γ-secretase modulators is disclosed. Starting from a triterpene glycoside γ-secretase modulator that gave a very low brain-to-plasma ratio, initial SAR and optimization involved replacement of a pendant sugar with a series of morpholines. This modification led to two compounds with significantly improved central nervous system (CNS) exposure.",

keywords = "γ-secretase, Alzheimer's disease, amyloid β, black cohosh, modulator",

author = "Fuller, {Nathan O.} and Hubbs, {Jed L.} and Austin, {Wesley F.} and Creaser, {Steffen P.} and McKee, {Timothy D.} and Loureiro, {Robyn M.B.} and Barbara Tate and Weiming Xia and Ives, {Jeffrey L.} and Findeis, {Mark A.} and Bronk, {Brian S.}",

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T1 - Initial optimization of a new series of γ-secretase modulators derived from a triterpene glycoside

AU - Fuller, Nathan O.

AU - Hubbs, Jed L.

AU - Austin, Wesley F.

AU - Creaser, Steffen P.

AU - McKee, Timothy D.

AU - Loureiro, Robyn M.B.

AU - Tate, Barbara

AU - Xia, Weiming

AU - Ives, Jeffrey L.

AU - Findeis, Mark A.

AU - Bronk, Brian S.

PY - 2012/11/8

Y1 - 2012/11/8

N2 - The discovery of a new series of γ-secretase modulators is disclosed. Starting from a triterpene glycoside γ-secretase modulator that gave a very low brain-to-plasma ratio, initial SAR and optimization involved replacement of a pendant sugar with a series of morpholines. This modification led to two compounds with significantly improved central nervous system (CNS) exposure.

AB - The discovery of a new series of γ-secretase modulators is disclosed. Starting from a triterpene glycoside γ-secretase modulator that gave a very low brain-to-plasma ratio, initial SAR and optimization involved replacement of a pendant sugar with a series of morpholines. This modification led to two compounds with significantly improved central nervous system (CNS) exposure.

KW - γ-secretase

KW - Alzheimer's disease

KW - amyloid β

KW - black cohosh

KW - modulator

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ER -

Initial optimization of a new series of γ-secretase modulators derived from a triterpene glycoside

Abstract

Keywords

ASJC Scopus subject areas

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