Discovery of (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor

• Published in: Journal of medicinal chemistry 2009-03, Vol.52 (6), p.1522-1524
• Main Authors: Man, Hon-Wah, Schafer, Peter, Wong, Lu Min, Patterson, Rebecca T, Corral, Laura G, Raymon, Heather, Blease, Kate, Leisten, Jim, Shirley, Michael A, Tang, Yang, Babusis, Darius M, Chen, Roger, Stirling, Dave, Muller, George W
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Drug Discovery; Humans; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors - administration & dosage; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Rats; Stereoisomerism; Structure-Activity Relationship; Thalidomide - administration & dosage; Thalidomide - analogs & derivatives; Thalidomide - chemistry; Thalidomide - pharmacology; Tumor Necrosis Factor-alpha - antagonists & inhibitors
• ISSN: 1520-4804
• DOI: 10.1021/jm900210d

In this communication, we report the discovery of 1S (apremilast), a novel potent and orally active phosphodiesterase 4 (PDE4) and tumor necrosis factor-alpha 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.