title: The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent.
abstract: The subtle modification of a selection of Abeta42 inhibiting non-steroidal anti-inflammatory drugs (NSAIDs), through synthesis of the geminal dimethyl analogues, was anticipated to ablate their cyclooxygenase activity whilst maintaining Abeta42 inhibition. Methylflurbiprofen 6 exhibited similar in vitro Abeta42 inhibition to its parent NSAID Flurbiprofen and was further evaluated in the Tg2576 mouse model of Alzheimer's disease and an animal model of gastro-intestinal (GI) impairment, but proved unviable for further clinical development.
authors.affiliation: Department of Chemistry, Merck Research Laboratories, 3535 General Atomics Ct, San Diego, CA 92121, USA. nick.stock@amirapharm.com
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stock
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.forename: Jonathan D J
authors.initials: JD
authors.lastname: Wrigley
authors.forename: Mark S
authors.initials: MS
authors.lastname: Shearman
authors.forename: Dirk
authors.initials: D
authors.lastname: Beher
authors.forename: James
authors.initials: J
authors.lastname: Peachey
authors.forename: Toni L
authors.initials: TL
authors.lastname: Williamson
authors.forename: Gretchen
authors.initials: G
authors.lastname: Bain
authors.forename: Weichao
authors.initials: W
authors.lastname: Chen
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Jiang
authors.forename: René
authors.initials: R
authors.lastname: St-Jacques
authors.forename: Peppi
authors.initials: P
authors.lastname: Prasit
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005480:Flurbiprofen / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D005480:Flurbiprofen