In eukaryotes, the AMP-activated protein kinase (AMPK), a highly conserved serine/threonine kinase, functions as a critical metabolic sensor. AMPK is activated by the rising ADP/ATP and AMP/ATP ratios during conditions of energy depletion and also by increasing intracellular Ca2+. In response to metabolic stress, AMPK maintains energy homeostasis by phosphorylating and regulating proteins that are involved in many physiological process including glucose and fatty acid metabolism, transcription, cell growth, mitochondrial biogenesis and autophagy. Evidence is mounting that AMPK also plays a role in a number of pathways unrelated to energy metabolism. Increasing AMPK activity has been shown to protect against type-2 diabetes or ameliorate it. One strategy of activating AMPK is to inhibit PDE4. Novel compounds were synthesized and tested for PDE4 inhibitory activity. We discovered one PDE4 inhibitor, compound 91, that has PDE4 IC50 of approximately 1 uM. It is more potent than rolipram, the most commonly used PDE4 inhibitor on the market. Compound 91 is able to activate AMPK and increase mitochondrial biogenesis in C2C12 myotubes. Therefore, compound 91 may be useful for increasing mitochondrial function and insulin sensitivity in skeletal muscle.
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