Dahl Russell, Sergienko Eduard A, Su Ying, Mostofi Yalda S, Yang Li, Simao Ana Maria, Narisawa Sonoko, Brown Brock, Mangravita-Novo Arianna, Vicchiarelli Michael, Smith Layton H, O'Neill W Charles, Millán José Luis, Cosford Nicholas D P
Conrad Prebys Center for Chemical Genomics, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
J Med Chem. 2009 Nov 12;52(21):6919-25. doi: 10.1021/jm900383s.
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.
我们报告了组织非特异性碱性磷酸酶（TNAP）类药物小分子抑制剂的特性及优化情况，TNAP是一种在骨骼形成和生长过程中对细胞外基质钙化调节至关重要的酶。对小分子文库进行高通量筛选（HTS），从而鉴定出芳基磺酰胺是TNAP的有效且选择性抑制剂。确定了活性的关键结构要求，随后对这些化合物的体外活性和生物利用度参数（包括代谢稳定性和渗透性）进行了分析。测定了大鼠皮下注射先导系列成员后的血浆水平，证明了这些TNAP抑制剂作为全身活性治疗剂针对各种涉及软组织钙化疾病的潜力。该系列的一个代表性成员也在机理和动力学研究中得到了表征。
