Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1375954 | Bioorganic & Medicinal Chemistry Letters | 2009 | 4 Pages |
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 IC50 values as low as 5 nM. A representative of the series was characterized in kinetic studies and determined to have a mode of inhibition not previously observed for TNAP inhibitors.
Graphical abstractWe report the design and synthesis of a series of pyrazole derivatives, based on a screening hit, which are potent TNAP inhibitors with IC50 values as low as 5 nM.Figure optionsDownload full-size imageDownload as PowerPoint slide