Department of Chemistry, Korea University, Seoul 136-701, Republic of Korea.
Bioorg Med Chem Lett. 2011 Jan 1;21(1):435-9. doi: 10.1016/j.bmcl.2010.10.123. Epub 2010 Nov 2.
A new series of thiazolidine derivatives with an adamantyl group was synthesized and evaluated for their ability to inhibit 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). Our initial compound 5a showed a weak inhibitory activity. Significant improvements in potency were achieved by substituent modification. The potent compound 8g (E) showed good in vitro inhibitory activity toward human 11β-HSD1, selectivity toward 11β-HSD2, metabolic stability, pharmacokinetic, and safety profile. Furthermore, this compound significantly inhibited 11β-HSD1 activity in rat and monkey models, and showed improved glycemic control in KKAy mice.
合成了一系列带有金刚烷基的新型噻唑烷衍生物，并评价了它们抑制 11β-羟甾类脱氢酶 1（11β-HSD1）的能力。我们的初始化合物 5a 表现出较弱的抑制活性。通过取代基修饰显著提高了活性。强效化合物 8g（E）对人 11β-HSD1 具有良好的体外抑制活性，对 11β-HSD2 具有选择性，代谢稳定性好，药代动力学和安全性良好。此外，该化合物能显著抑制大鼠和猴子模型中的 11β-HSD1 活性，并改善 KKAy 小鼠的血糖控制。
