Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor

K.W. Gillman, J.E. Starrett, M.F. Parker, K. Xie, J.J. Bronson, L.R. Marcin, K.E. McElhone, C.P. Bergstrom, R.A. Mate, Richard Williams, J.E. Meredith, C.R. Burton, D.M. Barten, J.H. Toyn, S.B. Roberts, K.A. Lentz, J.G. Houston, R. Zaczek, C.F. Albright, C.P. DeciccoJ.E. Macor, R.E. Olson

Research output: Contribution to journalArticlepeer-review

133 Citations (Scopus)

Abstract

During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase (A beta 40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced A beta 40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.
Original languageEnglish
Pages (from-to)120-124
Number of pages5
JournalACS MEDICINAL CHEMISTRY LETTERS
Volume1
Issue number3
DOIs
Publication statusPublished - 10 Jun 2010

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

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