The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent.
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.
Stock
Nicholas
N
Department of Chemistry, Merck Research Laboratories, 3535 General Atomics Ct, San Diego, CA 92121, USA. nick.stock@amirapharm.com
Munoz
Benito
B
Wrigley
Jonathan D J
JD
Shearman
Mark S
MS
Beher
Dirk
D
Peachey
James
J
Williamson
Toni L
TL
Bain
Gretchen
G
Chen
Weichao
W
Jiang
Xiaohui
X
St-Jacques
René
R
Prasit
Peppi
P
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*
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D005480:Flurbiprofen