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

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

  • ACS Med Chem Lett. 2010 Mar 22;1(3):120-4. doi: 10.1021/ml1000239.
Kevin W Gillman 1,  John E Starrett Jr 1,  Michael F Parker 1,  Kai Xie 1,  Joanne J Bronson 1,  Lawrence R Marcin 1,  Kate E McElhone 1,  Carl P Bergstrom 1,  Robert A Mate 1,  Richard Williams 2,  Jere E Meredith Jr 3,  Catherine R Burton 3,  Donna M Barten 3,  Jeremy H Toyn 3,  Susan B Roberts 3,  Kimberley A Lentz 4,  John G Houston 3,  Robert Zaczek 3,  Charles F Albright 3,  Carl P Decicco 1,  John E Macor 1,  Richard E Olson 1
Affiliations

Affiliations

  • 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.
PMID: 24900185 DOI: 10.1021/ml1000239
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.

Figures
Products