Literature DB >> 24900406

Initial Optimization of a New Series of γ-Secretase Modulators Derived from a Triterpene Glycoside.

Nathan O Fuller1, Jed L Hubbs1, Wesley F Austin1, Steffen P Creaser1, Timothy D McKee1, Robyn M B Loureiro1, Barbara Tate1, Weiming Xia1, Jeffrey L Ives1, Mark A Findeis1, Brian S Bronk1.   

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.

Entities:  

Keywords:  Alzheimer’s disease; amyloid β; black cohosh; modulator; γ-secretase

Year:  2012        PMID： 24900406      PMCID： PMC4025870          DOI： 10.1021/ml300256p

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  29 in total

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3.  Secretion of the Notch-1 Abeta-like peptide during Notch signaling.

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4.  Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor.

Authors:  George H Searfoss; William H Jordan; David O Calligaro; Elizabeth J Galbreath; Linda M Schirtzinger; Brian R Berridge; Hong Gao; Marnie A Higgins; Patrick C May; Timothy P Ryan
Journal:  J Biol Chem       Date:  2003-08-29       Impact factor: 5.157

Review 5.  The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics.

Authors:  Eric Karran; Marc Mercken; Bart De Strooper
Journal:  Nat Rev Drug Discov       Date:  2011-08-19       Impact factor: 84.694

6.  Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial.

Authors:  Robert C Green; Lon S Schneider; David A Amato; Andrew P Beelen; Gordon Wilcock; Edward A Swabb; Kenton H Zavitz
Journal:  JAMA       Date:  2009-12-16       Impact factor: 56.272

Review 7.  The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.

Authors:  John Hardy; Dennis J Selkoe
Journal:  Science       Date:  2002-07-19       Impact factor: 47.728

8.  Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation.

Authors:  Gwendolyn T Wong; Denise Manfra; Frederique M Poulet; Qi Zhang; Hubert Josien; Thomas Bara; Laura Engstrom; Maria Pinzon-Ortiz; Jay S Fine; Hu-Jung J Lee; Lili Zhang; Guy A Higgins; Eric M Parker
Journal:  J Biol Chem       Date:  2004-01-06       Impact factor: 5.157

Review 9.  Activity of gamma-secretase on substrates other than APP.

Authors:  Alberto Lleó
Journal:  Curr Top Med Chem       Date:  2008       Impact factor: 3.295

10.  beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease.

Authors:  A E Roher; J D Lowenson; S Clarke; A S Woods; R J Cotter; E Gowing; M J Ball
Journal:  Proc Natl Acad Sci U S A       Date:  1993-11-15       Impact factor: 11.205
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  3 in total

1.  Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator.

Authors:  Joo In Jung; Ashleigh R Price; Thomas B Ladd; Yong Ran; Hyo-Jin Park; Carolina Ceballos-Diaz; Lisa A Smithson; Günther Hochhaus; Yufei Tang; Rajender Akula; Saritha Ba; Edward H Koo; Gideon Shapiro; Kevin M Felsenstein; Todd E Golde
Journal:  Mol Neurodegener       Date:  2015-07-14       Impact factor: 14.195

Review 2.  Natural Product and Natural Product-Derived Gamma Secretase Modulators from Actaea Racemosa Extracts.

Authors:  Mark A Findeis; Frank C Schroeder; Steffen P Creaser; Timothy D McKee; Weiming Xia
Journal:  Medicines (Basel)       Date:  2015-06-30

3.  Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models.

Authors:  Robyn M Loureiro; Jo Ann Dumin; Timothy D McKee; Wesley F Austin; Nathan O Fuller; Jed L Hubbs; Ruichao Shen; Jeff Jonker; Jeff Ives; Brian S Bronk; Barbara Tate
Journal:  Alzheimers Res Ther       Date:  2013-04-18       Impact factor: 6.982
  3 in total

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