Literature DB >> 24900404

Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease.

Wen-Lian Wu1, Martin Domalski1, Duane A Burnett1, Hubert Josien1, Thomas Bara1, Murali Rajagopalan1, Ruo Xu1, John Clader1, William J Greenlee1, Andrew Brunskill1, Lynn A Hyde1, Robert A Del Vecchio1, Mary E Cohen-Williams1, Lixin Song1, Julie Lee1, Giuseppe Terracina1, Qi Zhang1, Amin Nomeir1, Eric M Parker1, Lili Zhang1.   

Abstract

An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aβ40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aβ after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease.

Entities:  

Keywords:  Alzheimer’s disease; amyloid; clinical candidate; notch; γ-Secretase inhibitor

Year:  2012        PMID： 24900404      PMCID： PMC4025742          DOI： 10.1021/ml300044f

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


  13 in total

1.  Biochemical characterization of the gamma-secretase activity that produces beta-amyloid peptides.

Authors:  L Zhang; L Song; G Terracina; Y Liu; B Pramanik; E Parker
Journal:  Biochemistry       Date:  2001-04-24       Impact factor: 3.162

Review 2.  Alzheimer's disease.

Authors:  Jeffrey L Cummings
Journal:  N Engl J Med       Date:  2004-07-01       Impact factor: 91.245

3.  Design and synthesis of tricyclic sulfones as gamma-secretase inhibitors with greatly reduced Notch toxicity.

Authors:  Ruo Xu; David Cole; Ted Asberom; Tom Bara; Chad Bennett; Duane A Burnett; John Clader; Martin Domalski; William Greenlee; Lynn Hyde; Hubert Josien; Hongmei Li; Mark McBriar; Brian McKittrick; Andrew T McPhail; Dmitri Pissarnitski; Li Qiang; Murali Rajagopalan; Thavalakulamgar Sasikumar; Jing Su; Haiqun Tang; Wen-Lian Wu; Lili Zhang; Zhiqiang Zhao
Journal:  Bioorg Med Chem Lett       Date:  2010-02-23       Impact factor: 2.823

Review 4.  Alzheimer's disease: the amyloid cascade hypothesis.

Authors:  J A Hardy; G A Higgins
Journal:  Science       Date:  1992-04-10       Impact factor: 47.728

5.  Cyclic hydroxyamidines as amide isosteres: discovery of oxadiazolines and oxadiazines as potent and highly efficacious γ-secretase modulators in vivo.

Authors:  Zhong-Yue Sun; Theodros Asberom; Thomas Bara; Chad Bennett; Duane Burnett; Inhou Chu; John Clader; Mary Cohen-Williams; David Cole; Michael Czarniecki; James Durkin; Gioconda Gallo; William Greenlee; Hubert Josien; Xianhai Huang; Lynn Hyde; Nicholas Jones; Irina Kazakevich; Hongmei Li; Xiaoxiang Liu; Julie Lee; Malcolm Maccoss; Mihir B Mandal; Troy McCracken; Amin Nomeir; Robert Mazzola; Anandan Palani; Eric M Parker; Dmitri A Pissarnitski; Jun Qin; Lixin Song; Giuseppe Terracina; Monica Vicarel; Johannes Voigt; Ruo Xu; Lili Zhang; Qi Zhang; Zhiqiang Zhao; Xiaohong Zhu; Zhaoning Zhu
Journal:  J Med Chem       Date:  2011-12-08       Impact factor: 7.446

6.  Identification of presenilin 1-selective γ-secretase inhibitors with reconstituted γ-secretase complexes.

Authors:  Julie Lee; Lixin Song; Giuseppe Terracina; Thomas Bara; Hubert Josien; Theodros Asberom; Thavalakulamgar K Sasikumar; Duane A Burnett; John Clader; Eric M Parker; Lili Zhang
Journal:  Biochemistry       Date:  2011-05-13       Impact factor: 3.162

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.  Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease.

Authors:  Scott C Mayer; Anthony F Kreft; Boyd Harrison; Magid Abou-Gharbia; Madelene Antane; Suzan Aschmies; Kevin Atchison; Michael Chlenov; Derek C Cole; Thomas Comery; George Diamantidis; John Ellingboe; Kristi Fan; Rocco Galante; Cathleen Gonzales; Douglas M Ho; Molly E Hoke; Yun Hu; Donna Huryn; Uday Jain; Mei Jin; Kenneth Kremer; Dennis Kubrak; Melissa Lin; Peimin Lu; Ron Magolda; Robert Martone; William Moore; Aram Oganesian; Menelas N Pangalos; Alex Porte; Peter Reinhart; Lynn Resnick; David R Riddell; June Sonnenberg-Reines; Joseph R Stock; Shaiu-Ching Sun; Erik Wagner; Ting Wang; Kevin Woller; Zheng Xu; Margaret M Zaleska; Joseph Zeldis; Minsheng Zhang; Hua Zhou; J Steven Jacobsen
Journal:  J Med Chem       Date:  2008-12-11       Impact factor: 7.446

Review 9.  Notch signaling in T- and B-cell development.

Authors:  Freddy Radtke; Anne Wilson; H Robson MacDonald
Journal:  Curr Opin Immunol       Date:  2004-04       Impact factor: 7.486

Review 10.  Notch regulation of lymphocyte development and function.

Authors:  Freddy Radtke; Anne Wilson; Stephane J C Mancini; H Robson MacDonald
Journal:  Nat Immunol       Date:  2004-03       Impact factor: 25.606
View more
  1 in total

1.  Alzheimer's disease: presenilin 2-sparing γ-secretase inhibition is a tolerable Aβ peptide-lowering strategy.

Authors:  Tomas Borgegård; Susanne Gustavsson; Charlotte Nilsson; Santiago Parpal; Rebecka Klintenberg; Anna-Lena Berg; Susanne Rosqvist; Lutgarde Serneels; Samuel Svensson; Fredrik Olsson; Shaobo Jin; Hongmei Yan; Johanna Wanngren; Anders Jureus; Anna Ridderstad-Wollberg; Patrik Wollberg; Kenneth Stockling; Helena Karlström; Asa Malmberg; Johan Lund; Per I Arvidsson; Bart De Strooper; Urban Lendahl; Johan Lundkvist
Journal:  J Neurosci       Date:  2012-11-28       Impact factor: 6.167
  1 in total

北京卡尤迪生物科技股份有限公司 © 2022-2023.