Epac1 and Epac2, two isoforms of exchange proteins directly activated by cAMP (Epac), respond to the second messenger cAMP and regulate a wide variety of intracellular processes under physiological and pathophysiological circumstances. Accumulating studies support that Epac may represent new mechanism-based therapeutic targets for various human diseases. Novel Epac1- or Epac2-specific antagonists are desperately needed to discriminate their biological functions. Herein, we report the chemical design, synthesis, and pharmacological characterization of three different scaffolds as highly potent and selective antagonists of Epac2 with the aid of molecular docking. Several selective Epac2 inhibitors have been identified including HJC0350,  which has  an IC50 value of 0.3 �M and is about 160-fold more potent than cAMP. ESI-05 , HJC0338  and HJC0350 , selected from each series, have demonstrated no inhibition of Epac1-mediated Rap1-GDP exchange activity at 25 �M in the presence of equal concentration of cAMP, indicating that they are Epac2-specific antagonists.

Identification and characterization of small molecules as potent and specific Epac2 antagonists

244th National Meeting (2012)

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