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

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• 作者：Makoto Kamata ; ^{Kamata_Makoto@takeda.co.jp} ; Tohru Yamashita ; Asato Kina ; Masaaki Funata ; Atsushi Mizukami ; Masako Sasaki ; Akiyoshi Tani ; Miyuki Funami ; Nobuyuki Amano ; Kohji Fukatsu
• 关键词：Acetyl-CoA carboxylase ; ACC ; Spiro-piperidine ; Metabolic stability ; Lipophilicity
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 June, 2012
• 卷：22
• 期：11
• 页码：3643-3647
• 文件大小：1225 K

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.