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
  • 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.
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