title: Small conformationally restricted piperidine N-arylsulfonamides as orally active gamma-secretase inhibitors.
abstract: The design and development of a new class of small 2,6-disubstituted piperidine N-arylsulfonamide gamma-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease.
authors.affiliation: Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07302, USA. hubert.josien@spcorp.com
authors.forename: Hubert
authors.initials: H
authors.lastname: Josien
authors.forename: Thomas
authors.initials: T
authors.lastname: Bara
authors.forename: Murali
authors.initials: M
authors.lastname: Rajagopalan
authors.forename: Theodros
authors.initials: T
authors.lastname: Asberom
authors.forename: John W
authors.initials: JW
authors.lastname: Clader
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: Gwendolyn T
authors.initials: GT
authors.lastname: Wong
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D019540:Area Under Curve; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008968:Molecular Conformation; D008970:Molecular Weight; D010088:Oxidoreductases / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D010880:Piperidines; D013449:Sulfonamides; D003577:Cytochrome P-450 Enzyme System; C408695:Cyp3a41a protein, mouse; D010088:Oxidoreductases; D053829:Amyloid Precursor Protein Secretases