Novel Tetrahydroisoquinoline Derivatives with Inhibitory Activities against Acyl-CoA: Cholesterol Acyltransferase and Lipid Peroxidation

• Ohta Masaru

  Research Laboratories, Kyoto Pharmaceutical Industries, Ltd. Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University

• Takahashi Kenji

  Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.

• Kasai Masayasu

  Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.

• Shoji Yoshimichi

  Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.

• Kunishiro Kazuyoshi

  Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.

• Miike Tomohiro

  Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.

• Kanda Mamoru

  Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.

• Mukai Chisato

  Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University

• Shirahase Hiroaki

  Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.

抄録

To find a novel acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor with anti-lipid peroxidative activity, a series of tetrahydroisoquinoline derivatives were synthesized and evaluated. A compound with a N-(4-hydroxy-2,3,5-trimethylphenyl)carbamoyl moiety at the 3-position and an octanoyl moiety at the 2-position (7) was demonstrated to show anti-foam cell formation activity stronger than and anti-lipid peroxidative activity comparable to those of Pactimibe, while it was hardly absorbed orally. To increase its bioavailability, the acyl chain at the 2-position was shortened and various polar or basic moieties were introduced at the 7-position of 7. Among the synthesized derivatives, (S)-7-dimethylamino-N-(4-hydroxy-2,3,5-trimethylphenyl)-2-isobutyryl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide hydrochloride (21) showed about 16-fold stronger anti-foam cell formation activity, 3-fold stronger hepatic ACAT inhibitory activity, similar anti-low density lipoprotein (LDL) oxidative activity and 2-fold more potent protective activity against macrophage cell death by oxidative stress in comparison with Pactimibe. Compound 21 was efficiently absorbed after oral administration at 10 mg/kg in rats and dogs and its C_max values were higher than its IC₅₀ values for in vitro activities. In conclusion, a tetrahydroisoquinoline structure is a useful scaffold for designing a phenolic anti-oxidative ACAT inhibitor, and compound 21 is expected to effectively prevent atherosclerosis.

収録刊行物

• ＣＨＥＭＩＣＡＬ　＆　ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ　ＢＵＬＬＥＴＩＮ

  ＣＨＥＭＩＣＡＬ　＆　ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ　ＢＵＬＬＥＴＩＮ 58 (8), 1066-1076, 2010

  公益社団法人 日本薬学会

キーワード

• acyl-CoA: cholesterol acyltransferase
• tetrahydroisoquinoline
• foam cell formation
• lipid peroxidation
• oxidative stress-induced cell death
• Pactimibe

詳細情報

• CRID: 1390282679149841408
• NII論文ID: 130000299816
• NII書誌ID: AA00602100
• DOI: 10.1248/cpb.58.1066
• ISSN: 13475223
• ISSN: 00092363
• NDL書誌ID: 10764131
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I10764131
• Web Site: http://www.jstage.jst.go.jp/article/cpb/58/8/58_8_1066/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2011090172
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可