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

  • J Med Chem. 2009 Mar 26;52(6):1522-4. doi: 10.1021/jm900210d.
Hon-Wah Man  1 ,  Peter Schafer ,  Lu Min Wong ,  Rebecca T Patterson ,  Laura G Corral ,  Heather Raymon ,  Kate Blease ,  Jim Leisten ,  Michael A Shirley ,  Yang Tang ,  Darius M Babusis ,  Roger Chen ,  Dave Stirling ,  George W Muller
Affiliations
  • 1. Drug Discovery Department, Celgene Corporation, 86 Morris Avenue, Summit, New Jersey 07901, USA. [email protected]
PMID: 19256507 DOI: 10.1021/jm900210d
Abstract

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.

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