Michael A Reilly

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There is a substantial body of evidence indicating that beta-amyloid peptides (Abeta) are critical factors in the onset and development of Alzheimer's disease (AD). One strategy for combating AD is to reduce or eliminate the production of Abeta through inhibition of the gamma-secretase enzyme, which cleaves Abeta from the amyloid precursor protein (APP). We(More)
1. Histamine catabolism in vivo was studied in mice and rats; tissues from animals killed 2.5 min after intravenous injection of (14)C-histamine were assayed for (14)C-histamine and total (14)C. Aminoguanidine, a diamine oxidase inhibitor, and methylhistamine, an inhibitor of the histamine methylating enzyme, were used to evaluate the roles of these enzymes(More)
The antihistaminic activity of many antidepressant drugs is well documented in vitro but has not been investigated as thoroughly in vivo. In the course of an investigation of the roles of H1 and H2 receptors in histamine-induced adrenocorticotropic hormone (ACTH) release in rats, it was observed that several antidepressants were potent inhibitors of this(More)
Plaques in the parenchyma of the brain containing Abeta peptides are one of the hallmarks of Alzheimer's disease. These Abeta peptides are produced by the final proteolytic cleavage of the amyloid precursor protein by the intramembraneous aspartyl protease gamma-secretase. Thus, one approach to lowering levels of Abeta has been via the inhibition of the(More)
The development of potent gamma-secretase inhibitors having substituted heterocycles attached to a benzobicyclo[4.2.1]nonane core is described. This work led to the identification of [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methylpyrazol-3-yl)-5'-(2,2,2-trifluoroethyl)spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole](More)
The efficacy of gamma-secretase inhibitors in vivo has, to date, been generally assessed in transgenic mouse models expressing increased levels of amyloid-beta (Abeta) peptide thereby allowing the detection of changes in Abeta production. However, it is not clear whether the in vivo potency of gamma-secretase inhibitors is independent of the level of(More)
Plaques in the parenchyma of the brain containing A peptides are one of the hallmarks of Alzheimer’s disease. These A peptides are produced by the final proteolytic cleavage of the amyloid precursor protein by the intramembraneous aspartyl protease -secretase. Thus, one approach to lowering levels of A has been via the inhibition of the -secretase enzyme.(More)