Enhanced delivery of γ-secretase inhibitor DAPT into the brain via an ascorbic acid mediated strategy

Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce pathogenic Abeta peptides, is an attractive approach for the treatment of Alzheimer's disease. We designed a gamma-secretase inhibitor bearing an ascorbic acid moiety which allows a specific delivery of the drug to the brain. Through, on the one hand, Abeta peptide production measurements by specific in vitro assays (gamma-secretase cell free assay and cell based assay on HEK 293 APP transfected cells) and on the other hand through pharmacokinetic studies on animal models, the new inhibitor shows a good pharmacokinetic profile as well as a potent gamma-secretase inhibitory activity in vitro. From the obtained results, it is expected that drug will be mainly delivered to the CNS with a low diffusion in the peripheral tissues. Consequently the side effects of this gamma-secretase inhibitor on the immune cells could be reduced. 4351046a.pdf......Page 0 Back to our roots p1022......Page 1 Granular matter: A tale of tails p1041......Page 2 Invariant visual representation by single neurons in the human brain p1102......Page 3 Omphalosphere: New York 2057 p1136......Page 4 4351003a.pdf......Page 5 4351004a.pdf......Page 6 4351006a.pdf......Page 7 4351008a.pdf......Page 9 4351010a.pdf......Page 11 4351013a.pdf......Page 13 4351014a.pdf......Page 14 4351015a.pdf......Page 15 4351016a.pdf......Page 16 4351018a.pdf......Page 18 4351022a.pdf......Page 21 4351024a.pdf......Page 23 4351026a.pdf......Page 25 4351028c.pdf......Page 27 4351029a.pdf......Page 28 4351030a.pdf......Page 29 4351033a.pdf......Page 31 4351035a.pdf......Page 32 4351036a.pdf......Page 33 4351040a.pdf......Page 37 4351042a.pdf......Page 39 4351044a.pdf......Page 41 4351045-1.pdf......Page 42 4351045a.pdf......Page 44 4351046-3.pdf......Page 46 4351047.pdf......Page 48 4351052.pdf......Page 53 4351059.pdf......Page 60 4351067.pdf......Page 68 4351071.pdf......Page 72 4351075.pdf......Page 76 4351079.pdf......Page 80 4351083.pdf......Page 84 4351088.pdf......Page 89 4351091.pdf......Page 92 4351094.pdf......Page 95 4351098.pdf......Page 99 4351102.pdf......Page 103 4351108.pdf......Page 109 4351113.pdf......Page 114 4351117.pdf......Page 118 4351122.pdf......Page 123 4351126.pdf......Page 127 nj7045-1131a.pdf......Page 132 nj7045-1132a.pdf......Page 133 4351136a.pdf......Page 135