ABSTRACT
In the course of a programme aimed at identifying Nurr1/NOT agonists for potential treatment of Parkinson's disease, a few hits from high throughput screening were identified and characterized. A combined optimization pointed to a very narrow and stringent structure activity relationship. A comprehensive program of optimization led to a potent and safe candidate drug displaying neuroprotective and anti-inflammatory activity in several in vitro and in vivo models.
Subject(s)
Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacology , Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism , Parkinson Disease/drug therapy , Animals , Cell Line , Cricetinae , Drug Discovery , Gene Expression Regulation/drug effects , Homeodomain Proteins/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Mice , Microglia/drug effects , Molecular Structure , Neurons/drug effects , Nuclear Receptor Subfamily 4, Group A, Member 2/genetics , Rats , Retinoid X Receptors/genetics , Retinoid X Receptors/metabolismABSTRACT
In vivo electron paramagnetic resonance (EPR) imaging and spectroscopy are non-invasive technologies used to specifically detect and quantify paramagnetic species. However, the relative instability of spin probes such as triarylmethyl radicals limits their application to conduct oxygen quantification and mapping. In this study we encapsulated tetrathiatriarylmethyl radical (TAM; known as "Finland" probe) in Pluronic F-127 hydrogel (PF-127) in order to limit its degradation and evaluate its in vitro and in vivo EPR properties as a function of oxygen. Our results show that the EPR signal of encapsulated TAM in PF-127 hydrogel is similar to the one in solution. Although it is less sensitive to oxygen, it is suitable for oximetry. We also demonstrated that the incorporation of TAM in PF-127 hydrogel leads to an improved in vivo EPR stability of the radical under anesthesia. This new formulation enables high quality EPR imaging and oximetry and paves the way for the application of TAM radical-based probes in various biomedical fields.
Subject(s)
Electron Spin Resonance Spectroscopy , Hydrogels , Poloxamer/chemistry , Free Radicals , Oximetry , OxygenABSTRACT
The 3-chloropyridazine moiety was immobilized on a Wang resin, using two different methodologies. The first of these involved direct nucleophilic substitution of 3,6-dichloropyridazine with the alcoholate of Wang resin. The experimental conditions were optimized. The second method involved a Mitsunobu reaction between the Wang resin and 6-chloropyridazin-3-ol during which a problem of regioselectivity was observed. The so-obtained chloropyridazine-containing resins were subsequently reacted with various arylboronic acids under Suzuki conditions. Acid cleavage yielded 6-arylpyridazin-3(2H)-ones with high chemical purity.
