The (R)-enantiomer of CE3F4 is a preferential inhibitor of human exchange protein directly activated by cyclic AMP isoform 1 (Epac1).

Isoform 1 and isoform 2 of exchange protein directly activated by cAMP (Epac1 and Epac2) contribute to cAMP signaling in numerous cellular processes. Their guanine-nucleotide exchange factor (GEF) activity toward the small GTP-binding protein Rap1 is stimulated by the agonist cAMP. CE3F4, a tetrahydroquinoline analog, prevents Epac1 activation in vitro and in living cultured cells by inhibiting the GEF activity of Epac1.

Identification of a tetrahydroquinoline analog as a pharmacological inhibitor of the cAMP-binding protein Epac.

The cAMP-binding protein Epac is a therapeutic target for the treatment of various diseases such as cardiac hypertrophy and tumor invasion. This points out the importance to develop Epac inhibitors to better understand the involvement of these cAMP sensors in physiology and pathophysiology. Here, we have developed a functional fluorescence-based high-throughput assay with a Z' value around 0.

Diversity-oriented synthesis of polycyclic diazinic scaffolds.

An efficient and versatile synthesis of a polycyclic diazinic system starting from oxazine has been developed using a two-step Michael/retro Michael and cyclization sequence. The substrates were synthesized with good to high yields giving rapid access to molecular diversity.

Nucleophilic addition onto methyl-4H-1,4-oxazine-3-carboxylate moiety: short access to 1,4-diazine privileged substructures.

To determine the synthetic potential of the original 1,4-oxazine ring, which appears as a valuable building block for the synthesis of more complex derivatives, Michael-type nucleophilic additions were studied. According to the nature of the nucleophile, either acyclic or cyclic derivatives were isolated. In the presence of primary amines, a short and efficient access to diazinic hemiaminals was described.

Synthesis and reactivity of imide-derived bisvinyl phosphates. Reactivity of 2,6-disubstituted 1,4-dihydropyridines.

Symmetrical and unsymmetrical 2,6-disubstituted dihydropyridines were prepared in high yields under mild conditions using the Suzuki and Stille Pd-catalyzed coupling reactions of imide-derived bisvinyl phosphates with a range of aryl, heteroaryl, and alkenyl moieties. The alkylation reaction at C-4 easily afforded original tri- and tetrasubstituted dihydropyridines. Hydrolysis of the latter under acidic condition provided efficiently either open-chain 1,5-diketones or di- or trisubstituted pyridines.