Sidique Shyama, Ardecky Robert, Su Ying, Narisawa Sonoko, Brown Brock, Millán José Luis, Sergienko Eduard, Cosford Nicholas D P
Burnham Center for Chemical Genomics, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Bioorg Med Chem Lett. 2009 Jan 1;19(1):222-5. doi: 10.1016/j.bmcl.2008.10.107. Epub 2008 Oct 31.
Tissue-nonspecific alkaline phosphatase (TNAP) plays a central role in regulating extracellular matrix calcification during bone formation and growth. High-throughput screening (HTS) for small molecule TNAP inhibitors led to the identification of hits in the sub-micromolar potency range. We report the design, synthesis and in vitro evaluation of a series of pyrazole derivatives of a screening hit which are potent TNAP inhibitors exhibiting IC(50) values as low as 5nM. A representative of the series was characterized in kinetic studies and determined to have a mode of inhibition not previously observed for TNAP inhibitors.
组织非特异性碱性磷酸酶（TNAP）在骨骼形成和生长过程中调节细胞外基质钙化方面发挥着核心作用。针对小分子TNAP抑制剂的高通量筛选（HTS）导致鉴定出了微摩尔以下效力范围内的活性化合物。我们报告了一系列筛选活性化合物的吡唑衍生物的设计、合成及体外评估，这些衍生物是强效的TNAP抑制剂，IC（50）值低至5 nM。该系列中的一个代表性化合物在动力学研究中得到了表征，并确定其具有一种此前TNAP抑制剂未观察到的抑制模式。
