title: Substituted 4-morpholine N-arylsulfonamides as γ-secretase inhibitors.
abstract: The design, synthesis, SAR, and biological profile of a substituted 4-morpholine sulfonamide series of γ-secretase inhibitors (GSIs) were described. In several cases, the resulting series of GSIs reduced CYP liabilities and improved γ-secretase inhibition activity compared to our previous research series. Selected compounds demonstrated significant reduction of amyloid-β (Aβ) after acute oral dosing in a transgenic animal model of Alzheimer's disease (AD).
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: zhiqiang.zhao@merck.com.
authors: Zhiqiang
authors: Z
authors: Zhao
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Dmitri A
authors: DA
authors: Pissarnitski
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Hubert B
authors: HB
authors: Josien
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Thomas A
authors: TA
authors: Bara
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: John W
authors: JW
authors: Clader
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Hongmei
authors: H
authors: Li
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Mark D
authors: MD
authors: McBriar
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Murali
authors: M
authors: Rajagopalan
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Ruo
authors: R
authors: Xu
authors: Department of Neurobiology, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Giuseppe
authors: G
authors: Terracina
authors: Department of Neurobiology, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Lynn
authors: L
authors: Hyde
authors: Department of Neurobiology, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Lixin
authors: L
authors: Song
authors: Department of Neurobiology, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Lili
authors: L
authors: Zhang
authors: Department of Neurobiology, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Eric M
authors: EM
authors: Parker
authors: NMR Structure Elucidation, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Rebecca
authors: R
authors: Osterman
authors: NMR Structure Elucidation, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Alexei V
authors: AV
authors: Buevich
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D008297:Male; D051379:Mice; D009025:Morpholines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D009025:Morpholines; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; substituted 4-morpholine sulfonamide; γ-secretase inhibitor