Development of novel anti-atheroscleroic agents

新型抗动脉粥样硬化药物的开发

• 批准号: 12557220
• 负责人: NAKAYAMA Hitoshi
• 金额: $ 7.94万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557220/
• 关键词: sulfonylurea; glibenclamide; macrophage; CD36; ACAT inhibitors; cholesterol metabolism; scavenger receptors

We have found that glibendamide, a typical antidiabetic sulfonylurea, inhibits acyl CoA:cholesterol acyllransferase (ACAT) that plays a crucial role to esterify the intracellular free cholesterol and a trigger to form foamed cells in macrophage. In this project we aim to develop novel ACAT inhibitors that are distinct from conventional ones in chemical structures and properties, because the conventional drug candidates of chemically neutral in charge are worried about their adverse effects on adrenal grand. During the passed three years, we organized a team of bioorganic chemist, synthetic organic chemist, molecular pharmacologist, and professionals in in vivo evaluation of drugs, and incomputer-aided drug design. We are succeeded in creating several drug candidates that are eliminated inslin secrition activity and have unique characteristics for ACAT inhibition in term of selective deliverly to taget cells and organs. The compounds are preparing for the patents and we will open the detailed information after the patent issue is completed.

我们发现格列苯脲是一种典型的抗糖尿病磺酰脲类药物，可抑制酰基辅酶A：胆固醇酰基转移酶（ACAT），该酶在酯化细胞内游离胆固醇和巨噬细胞中形成泡沫细胞的触发因素中发挥着至关重要的作用。在这个项目中，我们的目标是开发化学结构和性质与传统药物不同的新型ACAT抑制剂，因为化学中性电荷的传统候选药物担心它们对肾上腺的不良影响。三年来，我们组建了一支由生物有机化学家、有机合成化学家、分子药理学家以及药物体内评价、计算机辅助药物设计方面的专业人士组成的团队。我们成功地创造了几种候选药物，这些药物消除了胰岛素分泌活性，并在选择性递送至目标细胞和器官方面具有独特的 ACAT 抑制特性。该化合物正在准备专利，待专利授权完成后我们将公开详细信息。

项目成果

K.Kawahara, et al.: "Induction of CHOP and apoptosis by nitric oxide in p53-deficient microglial cells"FEBS Lett.. 506(2). 135-139 (2001)

K.Kawahara 等人：“p53 缺陷型小胶质细胞中一氧化氮诱导 CHOP 和细胞凋亡”FEBS Lett.. 506(2)。

A.Kuniyasu, et al.: "CD36-mediated endocytic uptake of AGE in mouse 3T3-L1 and human subcutaneous adipocytes"FEBS Lett.. 537. 85-90 (2003)

A.Kuniyasu 等人：“CD36 介导的小鼠 3T3-L1 和人皮下脂肪细胞中 AGE 的内吞摄取”FEBS Lett.. 537. 85-90 (2003)

Efficient identification of photolabeled amino acids by immuno-purification and mass spectrometry.

通过免疫纯化和质谱有效鉴定光标记氨基酸。

• 发表时间: 2002
• 期刊: Biochem.J. (in press)
• 作者: K.Kawahara;et al.
• 通讯作者: et al.

A. Miyazaki, et al.: "Scavenger receptors that recognize advanced glycation end products."Trends Canliovasc. Med.. 12(6). 258-262 (2003)

A. Miyazaki 等人：“识别晚期糖基化终产物的清道夫受体。”Canliovasc 趋势。

CD36-mediated endocytic uptake of AGE in mouse 3T3-L1 and human subcutaneous adipocytes.

小鼠 3T3-L1 和人皮下脂肪细胞中 CD36 介导的 AGE 内吞摄取。

• 发表时间: 2003
• 期刊: FEBS Lett. 537
• 作者: A.Kuniyasu;et al.
• 通讯作者: et al.