Cushing鈥檚 Syndrome: Development of Highly Potent and Selective CYP11B1 Inhibitors of the (Pyridylmethyl)pyridine Type

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• 作者：Juliette Emmerich ; Qingzhong Hu ; Nina Hanke ; Rolf W. Hartmann
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 8, 2013
• 年：2013
• 卷：56
• 期：15
• 页码：6022-6032
• 全文大小：464K
• 年卷期：v.56,no.15(August 8, 2013)
• ISSN：1520-4804

文摘

Potent and selective CYP11B1 inhibitors could be promising therapeutics for the treatment of Cushing鈥檚 syndrome. Optimization of Ref 1 (5-((1H-imidazol-1-yl)methyl)-2-phenylpyridine) led to compound 44 (5-((5-methylpyridin-3-yl)methyl)-2-phenylpyridine) with a 50-fold improved IC₅₀ value of 2 nM toward human CYP11B1 and an enhanced inhibition of the rat enzyme (IC₅₀ = 2440 nM) compared to Ref 1 (IC₅₀ > 10000 nM). Furthermore, selectivities over CYP11B2, CYP17, and CYP19 were observed, as well as satisfying metabolic stability not only in human and rat plasma but also in liver S9 fraction. Investigation of cytotoxicity and inhibition of hepatic CYP2A6 and CYP3A4 showed that 44 fulfills first safety criteria and can be considered for further in vivo evaluation in rats.