title: Hydroxytriamides as potent gamma-secretase inhibitors.
abstract: Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of gamma-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent gamma-secretase inhibitors with an IC(50) <10 nM.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. prasad.chaturvedula@bms.com
authors.forename: C V C
authors.initials: CV
authors.lastname: Prasad
authors.forename: Owen B
authors.initials: OB
authors.lastname: Wallace
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Noonan
authors.forename: Charles P
authors.initials: CP
authors.lastname: Sloan
authors.forename: Wai
authors.initials: W
authors.lastname: Lau
authors.forename: Shikha
authors.initials: S
authors.lastname: Vig
authors.forename: Michael F
authors.initials: MF
authors.lastname: Parker
authors.forename: David W
authors.initials: DW
authors.lastname: Smith
authors.forename: Steven B
authors.initials: SB
authors.lastname: Hansel
authors.forename: Craig T
authors.initials: CT
authors.lastname: Polson
authors.forename: Donna M
authors.initials: DM
authors.lastname: Barten
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Felsenstein
authors.forename: Susan B
authors.initials: SB
authors.lastname: Roberts
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D004353:Drug Evaluation, Preclinical; D010450:Endopeptidases / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse