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

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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
Volume17
Issue number16
DOIs
Publication statusPublished - Aug 15 2009

Fingerprint

Anticholesteremic Agents
Sterol O-Acyltransferase
Bioactivity
Derivatives
Foam Cells
Foams
Liver
Protein Binding
pactimibe
indoline
methanesulfonamide
Rats
Blood Proteins
Cholesterol

Keywords

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

ASJC Scopus subject areas

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

Cite this

Novel indoline-based acyl-CoA : cholesterol acyltransferase inhibitor: Effects of introducing a methanesulfonamide group on physicochemical properties and biological activities. / Shoji, Yoshimichi; Takahashi, Kenji; Ohta, Masaru; Kasai, Masayasu; Kunishiro, Kazuyoshi; Kanda, Mamoru; Yogai, Satoko; Takeuchi, Yasuo; Shirahase, Hiroaki.

In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 16, 15.08.2009, p. 6020-6031.

Research output: Contribution to journalArticle

Shoji, Yoshimichi ; Takahashi, Kenji ; Ohta, Masaru ; Kasai, Masayasu ; Kunishiro, Kazuyoshi ; Kanda, Mamoru ; Yogai, Satoko ; Takeuchi, Yasuo ; Shirahase, Hiroaki. / Novel indoline-based acyl-CoA : cholesterol acyltransferase inhibitor: Effects of introducing a methanesulfonamide group on physicochemical properties and biological activities. In: Bioorganic and Medicinal Chemistry. 2009 ; Vol. 17, No. 16. pp. 6020-6031.
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AU - Ohta, Masaru

AU - Kasai, Masayasu

AU - Kunishiro, Kazuyoshi

AU - Kanda, Mamoru

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AU - Takeuchi, Yasuo

AU - Shirahase, Hiroaki

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AB - 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.

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