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ACS Med Chem Lett. 2010 Mar 22;1(3):120-4. doi: 10.1021/ml1000239. eCollection 2010 Jun 10.

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

Author information

1
Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492.
2
Medicinal Chemistry Department, Albany Molecular Research Incorporated, 26 Corporate Circle, Albany, New York 15098.
3
Neuroscience Discovery Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492.
4
Metabolism and Pharmacokinetics, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492.

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.

KEYWORDS:

Alzheimer's; amyloid; brain penetrant; clinical candidate; oxadiazole; γ-Secretase

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