Novel antiarthritic agents with 1,2-isothiazolidine-1,1-dioxide (gamma-sultam) skeleton: cytokine suppressive dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase

  • J Med Chem. 2000 May 18;43(10):2040-8. doi: 10.1021/jm9906015.
M Inagaki  1 ,  T Tsuri ,  H Jyoyama ,  T Ono ,  K Yamada ,  M Kobayashi ,  Y Hori ,  A Arimura ,  K Yasui ,  K Ohno ,  S Kakudo ,  K Koizumi ,  R Suzuki ,  S Kawai ,  M Kato ,  S Matsumoto
Affiliations
  • 1. Shionogi Research Laboratories, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553-0002, Japan.
PMID: 10821716 DOI: 10.1021/jm9906015
Abstract

Various 1,2-isothiazolidine-1,1-dioxide (gamma-sultam) derivatives containing an antioxidant moiety, 2,6-di-tert-butylphenol substituent, were prepared. Some compounds, which have a lower alkyl group at the 2-position of the gamma-sultam skeleton, showed potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), as well as production of interleukin (IL)-1 in in vitro assays. They also proved to be effective in several animal arthritic models without any ulcerogenic activities. Among these compounds, (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1, 2-isothiazolidine-1,1-dioxide (S-2474) was selected as an antiarthritic drug candidate and is now under clinical trials. The structure-activity relationships (SAR) examined and some pharmacological evaluations are described.