Design, synthesis, and structure-activity relationships of novel spiro-piperidines as acetyl-CoA carboxylase inhibitors

被引：47

作者：

Kamata, Makoto ^{[1
]}

Yamashita, Tohru ^{[1
]}

Kina, Asato ^{[1
]}

Funata, Masaaki ^{[1
]}

Mizukami, Atsushi ^{[1
]}

Sasaki, Masako ^{[1
]}

Tani, Akiyoshi ^{[1
]}

Funami, Miyuki ^{[1
]}

Amano, Nobuyuki ^{[1
]}

Fukatsu, Kohji ^{[1
]}

机构：

[1] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Fujisawa, Kanagawa 2518555, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 11期

关键词：

Acetyl-CoA carboxylase; ACC; Spiro-piperidine; Metabolic stability; Lipophilicity; MALONYL-COA; OBESITY; SERIES; KINASE;

D O I：

10.1016/j.bmcl.2012.04.047

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Spiro-lactone (S)-1 is a potent acetyl-CoA carboxylase (ACC) inhibitor and was found to be metabolically liable in human hepatic microsomes. To remove one of the risk factors in human study by improving the metabolic stability, we focused on modifying the spiro-lactone ring and the benzothiophene portion of the molecule. Spiro-imide derivative 8c containing a 6-methylthieno[2,3-b]pyridine core exhibited potent ACC inhibitory activity and favorable pharmacokinetic profiles in rats. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：3643 / 3647

页数：5

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