Novel indoline-based acyl-CoA: cholesterol acyltransferase inhibitor: Effects of introducing a methanesulfonamide group on physicochemical properties and biological activities

Yoshimichi Shoji, Kenji Takahashi, Masaru Ohta, Masayasu Kasai, Kazuyoshi Kunishiro, Mamoru Kanda, Satoko Yogai, Yasuo Takeuchi, Hiroaki Shirahase

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A novel series of indoline-based acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors with a methanesulfonamide group at the 5-position were synthesized and their lipophilicity and biological activities were evaluated. Hepatic ACAT inhibitory and anti-foam cell formation activity increased dependent on lipophilicity of derivatives with various alkyl chains at the 1-position. The log D7.0-biological activity curve of the derivatives with a methanesulfonamide group shifted leftward compared to that of Pactimibe derivatives with a carboxymethyl group, and derivatives with no substituent, suggesting that a methanesulfonamide group plays an important role in the interaction with ACAT protein. Among derivatives, N-(1-ethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1b) had about twofold lower log D7.0 than Pactimibe, while it showed twofold higher hepatic ACAT inhibition than and the same anti-foam cell formation as Pactimibe, respectively. The Cmax of 1b (10 mg/kg, po) was higher than that of Pactimibe in rats. The plasma protein binding ratio of 1b was lower than that of Pactimibe: 64.8% and 97.9%, respectively. Compound 1b showed greater inhibitory effects on hepatic cholesterol secretion in mice than Pactimibe. In conclusion, the introduction of a methanesulfonamide group is effective to design less lipophilic, more efficacious and more bioavailable indoline-based ACAT inhibitors than previous indoline-based inhibitors.

Original languageEnglish
Pages (from-to)6020-6031
Number of pages12
JournalBioorganic and Medicinal Chemistry
Issue number16
Publication statusPublished - Aug 15 2009



  • ACAT inhibitor
  • Anti-foam cell formation
  • Lipophilicity
  • Methanesulfonamide derivatives
  • Pactimibe

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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