Piperidine-derived gamma-secretase modulators.
This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.
Hall
Adrian
A
Neurosciences Centre of Excellence for Drug Discovery, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. adian_hall@eisai.net
Elliott
Richard L
RL
Giblin
Gerard M P
GM
Hussain
Ishrut
I
Musgrave
James
J
Naylor
Alan
A
Sasse
Rosemary
R
Smith
Beverley
B
D000085:Acetates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004285:Dogs; D006801:Humans; D051379:Mice; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000187:drug effects
C568281:(1-(4-methyl-1-(6-(trifluoromethyl)-3-pyridinyl)pentyl)-2-(4-(trifluoromethyl)phenyl)-4-piperidinyl)acetic acid; D000085:Acetates; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010880:Piperidines; C078639:amyloid beta-protein (1-38); C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C032727:piperidine; D053829:Amyloid Precursor Protein Secretases