Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors

被引：44

作者：

Kamata, Makoto ^{[1
]}

Yamashita, Tohru ^{[1
]}

Kina, Asato ^{[1
]}

Tawada, Michiko ^{[1
]}

Endo, Satoshi ^{[1
]}

Mizukami, Atsushi ^{[1
]}

Sasaki, Masako ^{[1
]}

Tani, Akiyoshi ^{[1
]}

Nakano, Yoshihide ^{[1
]}

Watanabe, Yuuki ^{[1
]}

Furuyama, Naoki ^{[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 / 14期

关键词：

Acetyl-CoA carboxylase; ACC; Spiro-pyrazolidinedione; Spiro-pyrazolo[1,2-a]pyridazine; Obesity; Fatty acid oxidation; MALONYL-COA; KINASE;

D O I：

10.1016/j.bmcl.2012.05.062

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Spiro-pyrazolidinedione derivatives without quaternary chiral center were discovered by structure-based drug design and characterized as potent acetyl-CoA carboxylase (ACC) inhibitors. The high metabolic stability of the spiro-pyrazolo[1,2-a] pyridazine scaffold and enhancement of the activity by incorporation of a 7-methoxy group on the benzothiophene core successfully led to the identification of compound 4c as an orally bioavailable and highly potent ACC inhibitor. Oral administration of 4c significantly decreased the values of the respiratory quotient in rats, indicating the stimulation of fatty acid oxidation. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：4769 / 4772

页数：4

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