Department of Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
Department of Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
Bioorg Med Chem Lett. 2014 Jan 15;24(2):654-60. doi: 10.1016/j.bmcl.2013.11.066. Epub 2013 Dec 5.
A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11β-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11β-HSD1 enzyme. Optimization of two regions of A, R(1) and R(2) respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11β-HSD1 with a favorable development profile.
一系列 2-金刚烷基甲基四唑，其金刚烷环的 2-位带有季碳原子（即结构 A），被设计并合成作为新型、有效和选择性的人 11β-HSD1 酶抑制剂。基于 SAR 和对接实验，我们首次报道了四唑部分作为抑制 11β-HSD1 酶活性的药效团。对 A 的两个区域 R(1)和 R(2)分别进行优化，重点是提高人源和鼠源中抑制剂的活性（IC50）和微粒体稳定性。这些努力导致了 26 的鉴定，这是一种具有良好开发前景的人源 11β-HSD1 的口服生物利用抑制剂。
