A new series of potent benzodiazepine gamma-secretase inhibitors.
A new series of benzodiazepine-containing gamma-secretase inhibitors with potential use in the treatment of Alzheimer's disease is disclosed. Structure-activity relationships of the pendant hydrocinnamate side-chain which led to the preparation of highly potent inhibitors are described.
Churcher
Ian
I
Department of Medicinal Chemistry, The Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Essex Harlow, CM20 2QR, UK. ian_churcher@merck.com
Ashton
Kate
K
Butcher
John W
JW
Clarke
Earl E
EE
Harrison
Timothy
T
Lewis
Huw D
HD
Owens
Andrew P
AP
Teall
Martin R
MR
Williams
Susie
S
Wrigley
Jonathan D J
JD
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007202:Indicators and Reagents; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D011480:Protease Inhibitors; D001569:Benzodiazepines; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human