Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists.

A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with K(i(CAP))=0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 44S in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region.

Discovery of an Orally Bioavailable Benzofuran Analogue That Serves as a ß-Amyloid Aggregation Inhibitor for the Potential Treatment of Alzheimer's Disease.

We developed an orally active and blood-brain-barrier-permeable benzofuran analogue (8, MDR-1339) with potent antiaggregation activity. Compound 8 restored cellular viability from Aß-induced cytotoxicity but also improved the learning and memory function of AD model mice by reducing the Aß aggregates in the brains. Given the high bioavailability and brain permeability demonstrated in our pharmacokinetic studies, 8 will provide a novel scaffold for an Aß-aggregation inhibitor that may offer an alternative treatment for AD.

Application of ionic liquid to polymorphic transformation of anti-viral/HIV drug adefovir dipivoxil.

Ionic liquids (ILs) are defined as salts with a melting point below 100 °C. ILs have received increasing attention as new alternative to organic solvents because of their unique physicochemical properties. Therefore, this study was conducted in the purpose to present the efficacy of ILs as new solvents capable to control the Polymorphic transformation phenomenon. Here, the polymorphic transformation phenomenon of adefovir dipivoxil, an efficient antiviral active pharmaceutical ingredient on human immunodeficiency virus, was investigated. The phase transformation phenomenon from the metastable polymorph, new form (NF) to the stable polymorph, Form-X in 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF4) and 1-butyl-2,3-dimethylimidazolium tetrafluoroborate (BDMImBF4) ILs solutions was observed utilizing the solvent-mediated phase transformation method The thermodynamic factors, AEImBF4/BDMImBF4 solvent composition ratio of 3:7-6:4 and the temperature in range of 25-100 °C, as well as the dynamic factor, the rational speed in range of 300-1000 rpm were parameters studied in this experiment. The thermodynamic and dynamic equations involving nucleation and mass transfer were applied for the quantitative analysis. The result of the present study confirmed the use of ILs as substitute solvent for volatile organic solvents, and demonstrated the efficacy of ILs as potential solvent-media to control the polymorphic transformation.

Organotypic spinal cord slice culture to study neural stem/progenitor cell microenvironment in the injured spinal cord.

The molecular microenvironment of the injured spinal cord does not support survival and differentiation of either grafted or endogenous NSCs, restricting the effectiveness of the NSC-based cell replacement strategy. Studying the biology of NSCs in in vivo usually requires a considerable amount of time and cost, and the complexity of the in vivo system makes it difficult to identify individual environmental factors. The present study sought to establish the organotypic spinal cord slice culture that closely mimics the in vivo environment. The cultured spinal cord slices preserved the cytoarchitecture consisting of neurons in the gray matter and interspersed glial cells. The majority of focally applied exogenous NSCs survived up to 4 weeks. Pre-exposure of the cultured slices to a hypoxic chamber markedly reduced the survival of seeded NSCs on the slices. Differentiation into mature neurons was severely limited in this co-culture system. Endogenous neural progenitor cells were marked by BrdU incorporation, and applying an inflammatory cytokine IL-1ß significantly increased the extent of endogenous neural progenitors with the oligodendrocytic lineage. The present study shows that the organotypic spinal cord slice culture can be properly utilized to study molecular factors from the post-injury microenvironment affecting NSCs in the injured spinal cord.

Ex vivo VEGF delivery by neural stem cells enhances proliferation of glial progenitors, angiogenesis, and tissue sparing after spinal cord injury.

The present study was undertaken to examine multifaceted therapeutic effects of vascular endothelial growth factor (VEGF) in a rat spinal cord injury (SCI) model, focusing on its capability to stimulate proliferation of endogenous glial progenitor cells. Neural stem cells (NSCs) can be genetically modified to efficiently transfer therapeutic genes to diseased CNS. We adopted an ex vivo approach using immortalized human NSC line (F3 cells) to achieve stable and robust expression of VEGF in the injured spinal cord. Transplantation of NSCs retrovirally transduced to overexpress VEGF (F3.VEGF cells) at 7 days after contusive SCI markedly elevated the amount of VEGF in the injured spinal cord tissue compared to injection of PBS or F3 cells without VEGF. Concomitantly, phosphorylation of VEGF receptor flk-1 increased in F3.VEGF group. Stereological counting of BrdU+ cells revealed that transplantation of F3.VEGF significantly enhanced cellular proliferation at 2 weeks after SCI. The number of proliferating NG2+ glial progenitor cells (NG2+/BrdU+) was also increased by F3.VEGF. Furthermore, transplantation of F3.VEGF increased the number of early proliferating cells that differentiated into mature oligodendrocytes, but not astrocytes, at 6 weeks after SCI. F3.VEGF treatment also increased the density of blood vessels in the injured spinal cord and enhanced tissue sparing. These anatomical results were accompanied by improved BBB locomotor scores. The multifaceted effects of VEGF on endogenous gliogenesis, angiogenesis, and tissue sparing could be utilized to improve functional outcomes following SCI.