MEDI 262 |
| A growing body of evidence supports the utility of PDE4 inhibitors for treating Alzheimer's disease and other neurodegenerative and neuropsychiatric diseases by enhancing synaptic plasticity. PDE4 is an enzyme that regulates intracellular concentrations of cAMP, an important second messenger, by catalyzing its hydrolysis to AMP. Selective inhibition of PDE4 is one method to increase levels of cAMP and enhance synaptic plasticity. This enzyme is localized within key brain structures associated with learning and memory such as the hippocampus and prefrontal cortex. Increasing cAMP concentrations within these structures drives the PKA-CREB pathway leading ultimately to the synthesis of proteins that help to strengthen connections among neurons and enhance synaptic plasticity. Rolipram, the first generation prototypical selective PDE4 inhibitor was developed originally for depression, but was discontinued due to several factors including the side effect of emesis, high in vivo clearance and synthetic issues. Second generation PDE4 inhibitors (e.g., Cilomilast and Roflumilast) have generally targeted peripheral indications with an inflammatory component such as asthma and COPD. This talk will discuss optimization strategies and approaches toward achieving ‘on target' mechanism of action with PDE4 inhibitors for CNS activity. |
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Phosphodiesterase Inhibitors
1:30 PM-5:00 PM, Wednesday, August 22, 2007 BCEC -- 213, Oral
Division of Medicinal Chemistry |