Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters









Database
Language
Publication year range
1.
Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease.
Mayer, Scott C; Kreft, Anthony F; Harrison, Boyd; Abou-Gharbia, Magid; Antane, Madelene; Aschmies, Suzan; Atchison, Kevin; Chlenov, Michael; Cole, Derek C; Comery, Thomas; Diamantidis, George; Ellingboe, John; Fan, Kristi; Galante, Rocco; Gonzales, Cathleen; Ho, Douglas M; Hoke, Molly E; Hu, Yun; Huryn, Donna; Jain, Uday; Jin, Mei; Kremer, Kenneth; Kubrak, Dennis; Lin, Melissa; Lu, Peimin; Magolda, Ron; Martone, Robert; Moore, William; Oganesian, Aram; Pangalos, Menelas N; Porte, Alex; Reinhart, Peter; Resnick, Lynn; Riddell, David R; Sonnenberg-Reines, June; Stock, Joseph R; Sun, Shaiu-Ching; Wagner, Erik; Wang, Ting; Woller, Kevin; Xu, Zheng; Zaleska, Margaret M; Zeldis, Joseph; Zhang, Minsheng; Zhou, Hua; Jacobsen, J Steven.
J Med Chem ; 51(23): 7348-51, 2008 Dec 11.
Article in English | MEDLINE | ID: mdl-19012391

ABSTRACT

SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.


Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Receptor, Notch1/metabolism , Sulfonamides/pharmacology , Thiophenes/pharmacology , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Animals , Crystallography, X-Ray , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Mice , Mice, Transgenic , Models, Molecular , Molecular Conformation , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Thiophenes/chemical synthesis , Thiophenes/chemistry
SEND TO:
Email
Export
Print
RSS
XML
SELECTION OF CITATIONS
SEARCH DETAIL