title: 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.
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Gillman
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: John E
authors.initials: JE
authors.lastname: Starrett
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Parker
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Kai
authors.initials: K
authors.lastname: Xie
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Marcin
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Kate E
authors.initials: KE
authors.lastname: McElhone
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Carl P
authors.initials: CP
authors.lastname: Bergstrom
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mate
authors.affiliation: Medicinal Chemistry Department, Albany Molecular Research Incorporated, 26 Corporate Circle, Albany, New York 15098.
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.affiliation: Neuroscience Discovery Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Jere E
authors.initials: JE
authors.lastname: Meredith
authors.affiliation: Neuroscience Discovery Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Burton
authors.affiliation: Neuroscience Discovery Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Barten
authors.affiliation: Neuroscience Discovery Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Toyn
authors.affiliation: Neuroscience Discovery Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Roberts
authors.affiliation: Metabolism and Pharmacokinetics, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Lentz
authors.affiliation: Neuroscience Discovery Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: John G
authors.initials: JG
authors.lastname: Houston
authors.affiliation: Neuroscience Discovery Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Robert
authors.initials: R
authors.lastname: Zaczek
authors.affiliation: Neuroscience Discovery Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Olson
keywords: Alzheimer's; amyloid; brain penetrant; clinical candidate; oxadiazole; γ-Secretase