In other words, the drug pharmacodynam ics could exceed its phar macokinetics with the potential outcome neither being a disease modifying therapeutic. Clearly, these are important issues to be addressed in future drug development investigations. Conclusion The studies summarized here have several important Compound 069A attenuates synaptic protein loss and behav interactions. Therefore, the use of the Minozac scaffold to exploit its potential for bioavailability and brain pene trance, and chemical diversifications that allowed use of interactions selective for p38 MAPK and Inhibitors,Modulators,Libraries p38 MAPK over the other p38 MAPK isozymes, appear to be the molecular basis of the Inhibitors,Modulators,Libraries in vivo efficacy of compound 069A. The study summarized here does not unequivocally address if the improved neurologic outcome is due solely to the in vivo inhibition of glia p38 MAPK and proinflam matory cytokine production.

For example, in vitro co cul ture studies have shown that inhibition Inhibitors,Modulators,Libraries Inhibitors,Modulators,Libraries of neuronal p38 MAPK prevented decreases in synaptophysin levels correlated with neuronal tau phosphorylation. Therefore, it is possible that inhibition of neuronal p38 MAPK activ ity by 069A may have contributed to some of the in vivo synaptic changes seen in the animal model studies reported here. However, this is not a major concern for therapeutic development, as the individual effects on glia proinflammatory cytokine production and neuronal sign aling would both contribute to the overall positive neuro logic effects observed. In fact, such multi functional effects in the CNS due to p38 MAPK inhibition in differ ent cell types might be advantageous for use in a variety of neurodegenerative disorders.

The in vivo behavior and functional effects of 069A allowed its use to test hypotheses in this study and the results provide a foundation for future drug development efforts. Inhibitors,Modulators,Libraries Targeting a protein kinase that can modulate gene transcription and translation allows the possibility that implications. First, the data provide in vivo evidence sup porting the hypothesis that the gene regulating, serine threonine protein kinase p38 MAPK is a potential thera peutic target for CNS disorders where elevated levels of proinflammatory cytokines have been implicated as a component of disease progression.

Second, the results presented here and previously demonstrate that distinct signal transduction cascades can be modulated by small molecules to achieve the same in vivo outcome, attenuation of up regulated brain www.selleckchem.com/products/AP24534.html proinflammatory cytokine production with resultant improvement in neu ropathology. Third, the methods and approach described here demonstrate that novel tools for in vivo CNS research can be readily developed by rational variations of existing drug scaffolds to produce analog molecules with the desired in vivo properties.