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.
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.
Man
Hon-Wah
HW
Drug Discovery Department, Celgene Corporation, 86 Morris Avenue, Summit, New Jersey 07901, USA. hwman@celgene.com
Schafer
Peter
P
Wong
Lu Min
LM
Patterson
Rebecca T
RT
Corral
Laura G
LG
Raymon
Heather
H
Blease
Kate
K
Leisten
Jim
J
Shirley
Michael A
MA
Tang
Yang
Y
Babusis
Darius M
DM
Chen
Roger
R
Stirling
Dave
D
Muller
George W
GW
D000284:Administration, Oral; D000818:Animals; D055808:Drug Discovery; D006801:Humans; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; C505730:apremilast