No abstract

models for PK and PK/PD analysis. APP-transgenic mice were used for chronic efficacy studies. Results: CNP520 is selective for BACE-1 over BACE-2 and highly selective over pepsin, cathepsin D & E, and renin. Low nanomolar inhibition of Ab and sAPPb release was observed in cell assays using wt-APP cells. The free fraction of CNP520 in the rat brain, and the concentration of CNP520 in the CSF, was comparable to unbound blood concentrations, indicating excellent brain penetration. Oral dosing of CNP520 reduced Ab in the rat brain by more than 80%. A single CNP520 dose in dogs reduced CSF Ab for 72 hours, in agreement with long terminal half-lives (9.5-23 hours) in animals. CNP520 did not induce any hair depigmentation when dosed to mice for 8 weeks at a dose for > 90% Ab reduction. No hypopigmentation was observed in chronic studies in transgenic mice, and during long-term toxicology studies. CNP520 was dosed into APP23 mice 6 months and showed dose-dependent reduction of Triton TX-100 soluble and insoluble Ab. At the high dose, the levels of deposited Ab40/42 were indistinguishable from baseline. Conclusions: Preclinical data predict that more than 80% Ab reduction can be reached in humans at steady state. CNP520 stopped further amyloid-b deposition in APP transgenic mice, indicating that the compound may be able to show long term efficacy against Ab deposition in humans.Background:Numerous studies have clearly demonstrated the role of tau oligomers in the initiation and progression of tau pathology in Alzheimer's disease (AD) and associated tauopathies. We have taken a highly differentiated approach to identify novel small molecule inhibitors of tau oligomer formation using proprietary AD relevant in vitro and cell assays, along with the htau mouse model. Here, we present recent progress in the identification of leads for in vivo efficacy and IND enabling studies. Methods:In vitro assays were developed to screen a compound library. Selected candidates identified in the primary screen were subjected to medicinal chemistry studies to identify potential lead compounds after characterization in secondary and cell based assays. A number of lead compounds were also tested in vivo to assess preliminary metabolic stability, pharmacokinetics, off-target activity and acute toxicity. An in vivo study in htau mice will be initiated using vehicle and three doses of a lead. Results: A number of small molecule inhibitors of tau oligomerization with high potency, drug-like properties and with IC50's in the nanomolar to micromolar range, have been identified. Preliminary metabolic stability using mouse liver microsomes showed a half-life in the range of hours for select compounds. In addition, certain compounds had a brain-plasma distribution of approximately 1:1 and were not toxic when administered daily by i.p. injection to wild type mice for 5 days. Conclusions: From an initial primary screen, we have performed lead optimization studies which have led to novel tau oligomerization inhibitors with improved properties.Background: ...

biogenesis include erythropoietin and pioglitazone. Erythropoietin activates eNOS, causing production of nitric oxide (NO), which then triggers transcription of genes involved in mitochondrial biogenesis (3). Thiazolidinediones, e.g., pioglitazone, induce mitochondrial biogenesis by increasing expression of PPAR-1a-coactivator, the principle regulator of mitochondrial biogenesis. (4). Treatment using concurrent combinations having different targets is more effective than sequentially using single agents. A clinical trial would test the hypothesis that a combination of lithium, erythropoietin, and pioglitazone, might impede the progression of MCI to AD, or of early to more advanced AD. Conclusions: Dysfunctional mitochondria underlie AD and may be disposed, by combining lithium, erythropoietin, and pioglitazone to enhance mitophagy, which then stimulates production of new organelles by enhancing mitochondrial biogenesis.

No abstract

No abstract