title: 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.
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.
authors.affiliation: Drug Discovery Department, Celgene Corporation, 86 Morris Avenue, Summit, New Jersey 07901, USA. hwman@celgene.com
authors.forename: Hon-Wah
authors.initials: HW
authors.lastname: Man
authors.forename: Peter
authors.initials: P
authors.lastname: Schafer
authors.forename: Lu Min
authors.initials: LM
authors.lastname: Wong
authors.forename: Rebecca T
authors.initials: RT
authors.lastname: Patterson
authors.forename: Laura G
authors.initials: LG
authors.lastname: Corral
authors.forename: Heather
authors.initials: H
authors.lastname: Raymon
authors.forename: Kate
authors.initials: K
authors.lastname: Blease
authors.forename: Jim
authors.initials: J
authors.lastname: Leisten
authors.forename: Michael A
authors.initials: MA
authors.lastname: Shirley
authors.forename: Yang
authors.initials: Y
authors.lastname: Tang
authors.forename: Darius M
authors.initials: DM
authors.lastname: Babusis
authors.forename: Roger
authors.initials: R
authors.lastname: Chen
authors.forename: Dave
authors.initials: D
authors.lastname: Stirling
authors.forename: George W
authors.initials: GW
authors.lastname: Muller
mesh_terms: 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*
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; C505730:apremilast