Discovery and Validation of a Series of Aryl Sulfonamides as Selective Inhibitors of Tissue-Nonspecific Alkaline Phosphatase (TNAP)

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• 作者：Russell Dahl ; Eduard A. Sergienko ; Ying Su ; Yalda S. Mostofi ; Li Yang ; Ana Maria Simao ; Sonoko Narisawa ; Brock Brown ; Arianna Mangravita-Novo ; Michael Vicchiarelli ; Layton H. Smith ; W. Charles O’
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：November 12, 2009
• 年：2009
• 卷：52
• 期：21
• 页码：6919-6925
• 全文大小：839K
• 年卷期：v.52,no.21(November 12, 2009)
• ISSN：1520-4804

文摘

We report the characterization and optimization of drug-like small molecule inhibitors of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme critical for the regulation of extracellular matrix calcification during bone formation and growth. High-throughput screening (HTS) of a small molecule library led to the identification of arylsulfonamides as potent and selective inhibitors of TNAP. Critical structural requirements for activity were determined, and the compounds were subsequently profiled for in vitro activity and bioavailability parameters including metabolic stability and permeability. The plasma levels following subcutaneous administration of a member of the lead series in rat was determined, demonstrating the potential of these TNAP inhibitors as systemically active therapeutic agents to target various diseases involving soft tissue calcification. A representative member of the series was also characterized in mechanistic and kinetic studies.