title: Piperidine-derived gamma-secretase modulators.
abstract: 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.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. adian_hall@eisai.net
authors.forename: Adrian
authors.initials: A
authors.lastname: Hall
authors.forename: Richard L
authors.initials: RL
authors.lastname: Elliott
authors.forename: Gerard M P
authors.initials: GM
authors.lastname: Giblin
authors.forename: Ishrut
authors.initials: I
authors.lastname: Hussain
authors.forename: James
authors.initials: J
authors.lastname: Musgrave
authors.forename: Alan
authors.initials: A
authors.lastname: Naylor
authors.forename: Rosemary
authors.initials: R
authors.lastname: Sasse
authors.forename: Beverley
authors.initials: B
authors.lastname: Smith
mesh_terms: 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
chemical_list: 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