Synthesis and structure-activity relationship of 2-adamantylmethyl tetrazoles as potent and selective inhibitors of human 11尾-hydroxysteroid dehydrogenase type 1 (11尾-HSD1)

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• 作者：Xiang-Yang Ye ; David Yoon ; Stephanie Y. Chen ; Akbar Nayeem ; Rajasree Golla ; Ramakrishna Seethala ; Mengmeng Wang ; Timothy Harper ; Bogdan G. Sleczka ; Atsu Apedo ; Yi-Xin Li ; Bin He ; Mark Kirby ; David A. Gordon ; Jeffrey A. Robl
• 关键词：11尾-Hydroxysteroid dehydrogenase type 1 (11尾-HSD1) ; Enzyme inhibitor ; Structure&ndash ; activity relationships (SAR)
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 January, 2014
• 年：2014
• 卷：24
• 期：2
• 页码：654-660
• 全文大小：2145 K

文摘

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 11尾-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 11尾-HSD1 enzyme. Optimization of two regions of A, R¹ and R² 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 11尾-HSD1 with a favorable development profile.