ABSTRACT
Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of ß-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of ß-amyloid peptides; one of which, Aß42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aß42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aß42 production in mice.
Subject(s)
Amides/chemical synthesis , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Piperidines/chemistry , Alzheimer Disease/drug therapy , Amides/pharmacology , Amyloid beta-Peptides/biosynthesis , Animals , Brain/drug effects , Brain/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Mice , Peptide Fragments/biosynthesisABSTRACT
Ferroelectric polarization switching of high aspect ratio (>80:1) PbZr(0.52)Ti(0.48)O(3) (PZT) microtubes with a wall thickness of ~200 nm was investigated. A charge-based technique was used to assess the dielectric and ferroelectric properties of individual mechanically-unconstrained PZT microtubes with interdigitated electrodes. An enhancement in the degree of ferroelastic (non-180 degrees ) domain wall motion was observed in the tubes relative to films of similar thickness on rigid substrates. The dielectric response of the tubes showed a Rayleigh-like ac field dependence over a wide temperature range; the extent of the extrinsic contribution to the dielectric response dropped as the temperature approached 10K, but remained finite. This work demonstrates a general methodology for directly electrically addressing small, unconstrained ferroelectric devices, extending the range of driving fields and temperatures over which these materials can be probed.
