Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors
Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors
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DOI：
10.1016/j.bmcl.2012.05.062
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发表时间：
2012-07-15
影响因子：
2.7
通讯作者：
Fukatsu, Kohji
中科院分区：
文献类型：
--
作者：
Kamata, Makoto;Yamashita, Tohru;Fukatsu, Kohji
通过基于结构的药物设计发现了不带四级手性中心的螺吡唑烷二酮衍生物，并将其鉴定为有效的乙酰辅酶A羧化酶（ACC）抑制剂。螺吡唑并[1,2-a]哒嗪支架的高代谢稳定性以及通过在苯并噻吩核心上掺入7-甲氧基来增强活性成功地导致化合物4c被鉴定为口服生物利用度高的高效ACC抑制剂。口服4c显着降低大鼠的呼吸商值，表明刺激脂肪酸氧化。 (C) 2012 Elsevier Ltd. 保留所有权利。
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.