Discovery of a Potent and Orally Available Acyl-CoA: Cholesterol Acyltransferase Inhibitor as an Anti-atherosclerotic Agent: (4-Phenylcoumarin)acetanilide Derivatives

• Ogino Masaki

  Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd.

• Fukui Seiji

  Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd.

• Nakada Yoshihisa

  Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd.

• Tokunoh Ryosuke

  Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd.

• Itokawa Shigekazu

  Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd.

• Kakoi Yuichi

  Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd.

• Nishimura Satoshi

  Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd.

• Sanada Tsukasa

  Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd.

• Fuse Hiromitsu

  Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd.

• Kubo Kazuki

  Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd.

• Wada Takeo

  Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd.

• Marui Shogo

  Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd.

抄録

Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular enzyme that catalyzes cholesterol esterification. ACAT inhibitors are expected to be potent therapeutic agents for the treatment of atherosclerosis. A series of potent ACAT inhibitors based on an (4-phenylcoumarin)acetanilide scaffold was identified. Evaluation of the structure–activity relationships of a substituent on this scaffold, with an emphasis on improving the pharmacokinetic profile led to the discovery of 2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (23), which exhibited potent ACAT inhibitory activity (IC₅₀=12 nM) and good pharmacokinetic profile in mice. Compound 23 also showed regressive effects on atherosclerotic plaques in apolipoprotein (apo)E knock out (KO) mice at a dose of 0.3 mg/kg per os (p.o.).

収録刊行物

• ＣＨＥＭＩＣＡＬ　＆　ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ　ＢＵＬＬＥＴＩＮ

  ＣＨＥＭＩＣＡＬ　＆　ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ　ＢＵＬＬＥＴＩＮ 59 (10), 1268-1273, 2011

  公益社団法人 日本薬学会

キーワード

• acyl-CoA: cholesterol acyltransferase inhibitor
• cholesterol
• atherosclerosis
• (4-phenylcoumarin)acetanilide

詳細情報

• CRID: 1390282679150787200
• NII論文ID: 130001087094
• NII書誌ID: AA00602100
• DOI: 10.1248/cpb.59.1268
• ISSN: 13475223
• ISSN: 00092363
• NDL書誌ID: 11250407
• Web Site: http://id.ndl.go.jp/bib/11250407
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I11250407
• Web Site: http://www.jstage.jst.go.jp/article/cpb/59/10/59_10_1268/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2012288560
• 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