Compounds and methods of treating neurological disorders
- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Benefits of technology
Problems solved by technology
Method used
Image
Examples
example 1
[0107]In the absence of disease modifying therapy for AD, and also because of dismal outcome from the recent clinical trials using secretase inhibitors (Doody, R S. et al., 2013, N. Eng. J. Med. 369, 341-350), we wanted to pursue novel mechanisms of action. Multiple lines of evidences now suggest that it is not only increased Aβ, but also decreased sAPPα levels equally play critical role in the pathogenesis of AD (Jonsson, T et al., 2012; 2012, Nature 488, 96-99; Kaden, D. et al., 2012, EMBO Mol. Med. 4, 647-659; Suh, J. et al., 2013, Neuron, 80, 385-401). Therefore, modulation of alternative molecular targets that may increase sAPPα levels without directly altering the activities of α-, β or γ-secretases preferably through trafficking of APP is likely a viable approach. Towards this goal, we developed an HTS-compatible cell-based assay on AlphaLISA technology.
[0108]Several thiazole derivatives including benfotiamine, rosiglitazone and pioglitazone have been shown to enhance memory ...
example 2
[0119]Starting from p-methylbenzhydrylamine hydrochloride (MBHA.HCl) resin; we developed different approaches toward the diversity oriented solid-phase parallel synthesis of different aminothiazole compounds 1-6 (Scheme 1) (Micheals, H A et al., 2014, ACS Comb. Sci. 16, 1-4; Nefzi, A et al., 2010, J. Org. Chem. 75, 7939-7941). 575 thiazole compounds were synthesized and were tested for sAPPα increasing activity using CHO cells stably expressing APP751 wt. For initial screenings we used a cell-based human sAPPα ELISA kit (cat#27734, IBL Co., ltd, Japan) following instructions from the manufacturer. The method involves sandwich ELISA and use of two specific antibodies and tetra methyl benzidine as a coloring agent. We used previously generated CHO cells stably expressing APP751 wt (7WD10 cells) for the secretion of sAPPα and Aβ in to the conditioned medium (CM). We first optimized the protocol for our cell culture conditions.
[0120]Among about 575 compounds tested, four compounds deriv...
example 3
Studies on Compound THPI-244 to Identify Lethal Dose, 50 (LD50) in Mice
[0122]Wild-type (WT) C57BL / 6 mice aged about 6 months were used in the study. The compound THPI-244 was initially dissolved in 100% DMSO and then diluted to final 10% DMSO with phosphate buffered saline (PBS). Injection of compound THPI-244 to 6 mice at 100 mg / kg body weight by intraperitoneal (i.p.) route did not result in the death of any of the 6 mice (monitored for 5 days). Among these 6 mice, 3 mice received repeated injections (i.p) of compound THPI-244 for 5 days. None of the mice showed any lethal effect. A single mouse was given an injection of compound THPI-244 at 200 mg / kg body weight and survived without visible ill effects. Although these results are preliminary, the study does indicate that compound THPI-244 can be injected at elevated doses to achieve the desired biological effects.
PUM
| Property | Measurement | Unit |
|---|---|---|
| Composition | aaaaa | aaaaa |
| Structure | aaaaa | aaaaa |
Abstract
Description
Claims
Application Information
Login to View More