Dataset Information

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

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.

SUBMITTER: Gillman KW

PROVIDER: S-EPMC4007960 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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

Gillman Kevin W KW Starrett John E JE Parker Michael F MF Xie Kai K Bronson Joanne J JJ Marcin Lawrence R LR McElhone Kate E KE Bergstrom Carl P CP Mate Robert A RA Williams Richard R Meredith Jere E JE Burton Catherine R CR Barten Donna M DM Toyn Jeremy H JH Roberts Susan B SB Lentz Kimberley A KA Houston John G JG Zaczek Robert R Albright Charles F CF Decicco Carl P CP Macor John E JE Olson Richard E RE

ACS medicinal chemistry letters 20100322 3

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 administrat ...[more]

PMID: 24900185

Dataset Information

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

Publications

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

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