期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 19, 期 1, 页码 222-225出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2008.10.107
关键词
Pyrazoles; Alkaline phosphatases; Competitive inhibitors; Hit-to-probe optimization
资金
- NIH [U54HG003916, DE12889]
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U54HG005033, U54HG003916] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH [R01DE012889] Funding Source: NIH RePORTER
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. Published by Elsevier Ltd.
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