Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor
ACS Medicinal Chemistry Letters2010Vol. 1(3), pp. 120–124
Citations Over TimeTop 10% of 2010 papers
Kevin W. Gillman, John E. Starrett, Michael F. Parker, Kai Xie, Joanne J. Bronson, Lawrence R. Marcin, Kate E. McElhone, Carl P. Bergstrom, Robert Mate, Richard D. Williams, Jere E. Meredith, Catherine R. Burton, Donna M. Barten, Jeremy H. Toyn, Susan B. Roberts, Kimberley A. Lentz, John G. Houston, Robert Zaczek, Charles F. Albright, Carl P. Decicco, John E. Macor, Richard E. Olson
Abstract
During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-β precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of γ-secretase (Aβ40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.
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