High affinity, bioavailable 3-amino-1,4-benzodiazepine-based gamma-secretase inhibitors.
In this paper, we describe the development of a novel series of high affinity, orally bioavailable 3-amino-1,4 benzodiazepine-based gamma-secretase inhibitors for the potential treatment of Alzheimer's disease. We disclose structure-activity relationships based around the 1, 3 and 5 positions of the benzodiazepine core structure.
Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. andrew_owens@merck.com
Andrew P
AP
Owens
Alan
A
Nadin
Adam C
AC
Talbot
Earl E
EE
Clarke
Timothy
T
Harrison
Huw D
HD
Lewis
Michael
M
Reilly
Jonathan D J
JD
Wrigley
José L
JL
Castro
D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy*; D000588:Amines / Q000138:chemical synthesis / Q000493:pharmacokinetics; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D001569:Benzodiazepines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D001711:Biotransformation; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000588:Amines; D004791:Enzyme Inhibitors; D001569:Benzodiazepines; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human