Arylsulfonamidopiperidone derivatives as a novel class of factor Xa inhibitors

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• 作者：Yan  ; Shi  ; ;   ; ^{yan.shi@bms.com} ; Stephen P.  ; O&rsquo ; Connor ; Doree  ; Sitkoff ; Jing  ; Zhang^&dagger ; ; Mengxiao  ; Shi ; Sharon N.  ; Bisaha ; Ying  ; Wang ; Chi  ; Li ; Zheming  ; Ruan ; R.  ; Michael Lawrence ; Herbert E.  ; Klei ; Kevin  ; Kish ; Eddie C.-K.  ; Liu ; Steve M.  ; Seiler ; Liang  ; Schweizer ; Thomas E.  ; Steinbacher ; William A.  ; Schumacher ; Jeffrey A.  ; Robl ; John E.  ; Macor ; Karnail S.  ; Atwal ; Philip D.  ; Stein
• 关键词：Factor Xa inhibitor ; Bioisostere ; Valerolactam ; Arylsulfonamide ; Antithrombotic agent ; X-ray crystal structure
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：15 December 2011
• 年：2011
• 卷：21
• 期：24
• 页码：7516-7521
• 全文大小：2167 K

文摘

The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide¨Cvalerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC₅₀ of 7 nM and EC_2¡ÁPT of 1.7 ¦ÌM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide¨Cvalerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets.