title: Discovery of amide and heteroaryl isosteres as carbamate replacements in a series of orally active gamma-secretase inhibitors.
abstract: The design of amide and heteroaryl amide isosteres as replacements for the carbamate substructure in previously disclosed 2,6-disubstituted piperidine N-arylsulfonamides is described. In several cases, amides lessened CYP liabilities in this class of gamma-secretase inhibitors. Selected compounds showed significant reduction of Abeta levels upon oral dosing in a transgenic murine model of Alzheimer's disease.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. mark.mcbriar@spcorp.com
authors.forename: Mark D
authors.initials: MD
authors.lastname: McBriar
authors.forename: John W
authors.initials: JW
authors.lastname: Clader
authors.forename: Inhou
authors.initials: I
authors.lastname: Chu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Del Vecchio
authors.forename: Leonard
authors.initials: L
authors.lastname: Favreau
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Hyde
authors.forename: Amin A
authors.initials: AA
authors.lastname: Nomeir
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Pissarnitski
authors.forename: Lixin
authors.initials: L
authors.lastname: Song
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002219:Carbamates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D010069:Oxadiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D016229:Amyloid beta-Peptides; D002219:Carbamates; D065607:Cytochrome P-450 Enzyme Inhibitors; D006571:Heterocyclic Compounds; D010069:Oxadiazoles; D010880:Piperidines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases