A novel series of potent gamma-secretase inhibitors based on a benzobicyclo[4.2.1]nonane core.
A new series of gamma-secretase inhibitors was developed from an in-house screening hit based on a benzobicyclo[4.2.1]nonane core. Lead optimisation studies led to the development of a series of potent inhibitors and in vivo efficacy was demonstrated.
Lewis
Stephen J
SJ
Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. stephen_lewis@merck.com
Smith
Adrian L
AL
Neduvelil
Joseph G
JG
Stevenson
Graeme I
GI
Lindon
Matthew J
MJ
Jones
A Brian
AB
Shearman
Mark S
MS
Beher
Dirk
D
Clarke
Earl
E
Best
Jonathan D
JD
Peachey
James E
JE
Harrison
Timothy
T
Castro
J Luis
JL
D000473:Alkanes / Q000138:chemical synthesis* / Q000494:pharmacology; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000577:Amides / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000473:Alkanes; D000577:Amides; D000588:Amines; D006571:Heterocyclic Compounds; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; C017573:nonane