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 language | English |
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Pages (from-to) | 120-124 |
Number of pages | 5 |
Journal | ACS MEDICINAL CHEMISTRY LETTERS |
Volume | 1 |
Issue number | 3 |
DOIs | |
Publication status | Published - 10 Jun 2010 |
ASJC Scopus subject areas
- Organic Chemistry
- Drug Discovery
- Biochemistry