Discovery of (S)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-lH-isoindol-4-y1}acetamide (Apremilast), a Potent and Orally Active Phosphodiesterase 4 and Tumor Necrosis Factor-a. Inhibitor

摘要

In this communication, we report the discovery of 1s (apremilast), a novel potent and orally active phosphodiesterase 4 (PDE4) and tumor necrosis factor-α inhibitor. The optimization of previously reported 3-( 1,3-dioxo-1 ,3-dihydroisoindol-2-yl)-3-(3,4-dimethoxyphenyl)propionic acid PDE4 inhibitors led to this series of sulfone analogues. Evaluation of the structure—activity relationship of substitutions on the phthalimide group led to the discovery of an acetylamino analogue 1s, which is currently in clinical trials.