Synthesis, in Vitro Covalent Binding Evaluation, and Metabolism of 14C-Labeled Inhibitors of 11尾-HSD1

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• 作者：Daqing Sun ; Qiuping Ye ; Xuelei Yan ; Yosup Rew ; Peter Fan ; Xiao He ; Min Jiang ; Dustin L. McMinn ; Mario Monshouwer ; Hua Tu ; Jay P. Powers
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：November 13, 2014
• 年：2014
• 卷：5
• 期：11
• 页码：1245-1250
• 全文大小：357K
• ISSN：1948-5875

文摘

In this letter, we reported the design and synthesis of three potent, selective, and orally bioavailable 11尾-HSD1 inhibitors labeled with ¹⁴C: AMG 456 (1), AM-6949 (2), and AM-7715 (3). We evaluated the covalent protein binding of the labeled inhibitors in human liver microsomes in vitro and assessed their potential bioactivation risk in humans. We then studied the in vitro mechanism of 2 in human hepatocytes and the formation of reactive intermediates. Our study results suggest that 1 and 3 have low potential for metabolic bioactivation in humans, while 2 has relatively high risk.

Keywords:

11尾-HSD1; 11尾-HSD2; diabetes; metabolic syndrome; hydroxysteroid dehydrogenase; arylsulfonylpiperazine; diarylsulfone; 4,4-disubstituted cyclohexylbenzamides; radiolabeled inhibitor; covalent protein binding; bioactiviation; reactive metabolite