title: Cyclic sulfamide gamma-secretase inhibitors.
abstract: A novel series of N-alkyl-substituted cyclic sulfamides were developed from a screening hit. Chemistries were developed which allowed surveys of N-alkyl groups and amines resulting in the identification of N-trifluoroethyl-substituted cyclic sulfamides with good in vitro and in vivo gamma-secretase activity. One compound with subnanomolar activity elicited a reduction in brain Abeta40 after oral dosing in APP-YAC mice.
authors.affiliation: Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. tim_sparey@merck.com
authors.forename: Tim
authors.initials: T
authors.lastname: Sparey
authors.forename: Dirk
authors.initials: D
authors.lastname: Beher
authors.forename: Jonathan
authors.initials: J
authors.lastname: Best
authors.forename: Mirlinda
authors.initials: M
authors.lastname: Biba
authors.forename: José L
authors.initials: JL
authors.lastname: Castro
authors.forename: Earl
authors.initials: E
authors.lastname: Clarke
authors.forename: Joanne
authors.initials: J
authors.lastname: Hannam
authors.forename: Timothy
authors.initials: T
authors.lastname: Harrison
authors.forename: Huw
authors.initials: H
authors.lastname: Lewis
authors.forename: Andrew
authors.initials: A
authors.lastname: Madin
authors.forename: Mark
authors.initials: M
authors.lastname: Shearman
authors.forename: Bindi
authors.initials: B
authors.lastname: Sohal
authors.forename: Nancy
authors.initials: N
authors.lastname: Tsou
authors.forename: Christopher
authors.initials: C
authors.lastname: Welch
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wrigley
mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001923:Brain Chemistry; D010450:Endopeptidases; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D006571:Heterocyclic Compounds; D011480:Protease Inhibitors; D013451:Sulfonic Acids; C005741:sulfamic acid; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse