Yumiko Uno

2-{3-[4-(Alkylsulfinyl)phenyl]-1-benzofuran-5-yl}-5-methyl-1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3beta with good brain permeability.

Glycogen synthase kinase 3beta (GSK-3beta) inhibition is expected to be a promising therapeutic approach for treating Alzheimers disease. Previously we reported a series of 1,3,4-oxadiazole derivatives as potent and highly selective GSK-3beta inhibitors, however, the representative compounds 1a,b showed poor pharmacokinetic profiles. Efforts were made to address this issue by reducing molecular weight and lipophilicity, leading to the identification of oxadiazole derivatives containing a sulfinyl group, (S)-9b and (S)-9c. These compounds exhibited not only highly selective and potent inhibitory activity against GSK-3beta but also showed good pharmacokinetic profiles including favorable BBB penetration. In addition, (S)-9b and (S)-9c given orally to mice significantly inhibited cold water stress-induced tau hyperphosphorylation in mouse brain.

A novel glycogen synthase kinase-3 inhibitor 2-methyl-5-(3-{4-[(S )-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole decreases tau phosphorylation and ameliorates cognitive deficits in a transgenic model of Alzheimer’s disease

J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07532.x

Efficacy of a novel, orally active GSK-3 inhibitor 6-Methyl-N-[3-[[3-(1-methylethoxy)propyl]carbamoyl]-1H-pyrazol-4-yl]pyridine-3-carboxamide in tau transgenic mice

Neurofibrillary tangles (NFTs) composed of hyperphosphorylated and aggregated tau are common pathological characteristics in Alzheimers disease (AD) and other tauopathies. Aberrant tau phosphorylation is an early and pivotal event in the pathogenesis of tauopathies, and since GSK-3 is a key factor implicated in aberrant tau phosphorylation, GSK-3 inhibition is expected to suppress tauopathy disease progression. In the present study, we report the efficacy of a newly discovered small molecule GSK-3 inhibitor, 6-methyl-N-[3-[[3-(1-methylethoxy)propyl]carbamoyl]-1H-pyrazol-4-yl]pyridine-3-carboxamide (compound A), to inhibit tau phosphorylation and to reduce the amount of pathological aggregated tau in JNPL3 mice that overexpress a mutant form of human tau. Compound A is a highly potent and selective inhibitor of GSK-3 with an IC(50) of 2 nM, with at least 230-fold lower potency against 27 other kinases. Oral administration of compound A resulted in a significant reduction of tau phosphorylation at several GSK-3 directed sites. Furthermore, chronic oral administration of compound A markedly reduced aggregated tau in old JNPL3 mice. These results suggest that a novel, orally active GSK-3 inhibitor, compound A, has potency in the prevention of tau pathology.

Increased 25-hydroxycholesterol concentrations in the lungs of patients with chronic obstructive pulmonary disease.

Background and objective:  25‐Hydroxycholesterol (25‐HC) is produced from cholesterol by the enzyme cholesterol 25‐hydroxylase and is associated with atherosclerosis of vessels. Recently, 25‐HC was reported to cause inflammation in various types of tissues. The aim of this study was to assess the production of 25‐HC in the airways and to elucidate the role of 25‐HC in neutrophil infiltration in the airways of patients with chronic obstructive pulmonary disease (COPD).

A novel glycogen synthase kinase-3 inhibitor 2-methyl-5-(3-{4-[(s)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole (mmbo) decreased tau phosphorylation and ameliorated cognitive deficits in a transgenic model of Alzheimer's disease

potential epitope specificity and safety of this promising therapeutic effect, we are examining several tau epitopes. Here we assessed the efficacy of using a pseudo-phosphorylated tau immunogen. Methods: Homozygous JNPL3 mice were immunized with Tau379-408[ESer396, E-Ser404] in alum adjuvant (n 1⁄4 13) or with adjuvant only (n 1⁄4 7), starting at 2 months. Mice were tested on various sensorimotor tasks (rotarod, traverse beam, locomotor activity and grip strength) at 5 and 8 months of age. Antibody titers were determined and at 8 months their brains were processed for tau biochemistry and histology. Results: The vaccine elicited a robust antibody response towards the immunogen, and its phosphorylated and non-phosphorylated analogs. Which is as expected since this region of the tau protein is highly immunogenic. The immunized mice had a 24% reduction in soluble PHF1/total tau ratio on western blots (p 1⁄4 0.04), and a 42% reduction in PHF1 immunostaining in the dentate gyrus (p < 0.03), compared to alum-treated mice. Levels of sarkosyl insoluble human and total tau were highly variable in both groups and not significantly different. Biochemical and histological analyses with other antibodies and of other brain regions is underway. Disappointingly, potential improvements in motor function of the immunized mice could not be assessed since the animals did not develop overt signs of such impairments at the ages tested, in contrast to our previous observation in the same homozygous model (Asuni A. et al., J. Neurosci., 2007). Unfortunately, such changes in phenotype are commonly observed in transgenic mice.Conclusions: These findings indicate that immunological targeting using a pseudo-phosphorylated tau epitope can reduce pathological tau within the brain, further supporting the feasibility of tau immunotherapy.

Efficacy of a novel, orally active GSK-3 Inhibitor 6-Methyl-N-[3-[[3-(1-methylethoxy)propyl]carbamoyl]-1H-pyrazol-4-yl]pyridine-3-carboxamide in tau transgenic mice

hibit phosphorylation of Tau on several AD-relevant Tau epitopes. 21,22 Specifically, at early stages (3 months of age), hyperphosphorylated Tau protein are visualized (AD2, AT270) in the hippocampus while abnormal Tau species (AT100, pS422) are faintly observed. Over the time, hippocampal pathology increases with strong AT100 and pS422 immuno reactivity’s at 8-10 months of age, ultimately correlated with prominent cognitive deterioration. Three months old THY-Tau22 mice were immunized with a peptide including the phosphoserine 422 residuewhile control mice received the adjuvant alone. After optimization, a protocol (time of immunization and peptide length) was set up and different parameters were analyzed. Results: A specific antibody response against the pSer422 epitope was observed. We noticed a decrease in insoluble tau species (AT100and pS422 immunoreactive) correlate with a significant memory improvement using the Y-maze spatial memory task. Conclusions: Overall, our data support that immunotherapy targeting pathological pSer422 epitope leads to a specific response against pathological Tau and may improve cognitive deficits promoted by Tau pathology.