Design and synthesis of pyrazole derivatives as potent and selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP)

被引：69

作者：

Sidique, Shyama ^{[1
]}

Ardecky, Robert ^{[1
]}

Su, Ying ^{[1
]}

Narisawa, Sonoko

Brown, Brock ^{[1
]}

Millan, Jose Luis

Sergienko, Eduard ^{[1
]}

Cosford, Nicholas D. P. ^{[1
]}

机构：

[1] Burnham Inst Med Res, Burnham Ctr Chem Genom, La Jolla, CA 92037 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 01期

关键词：

Pyrazoles; Alkaline phosphatases; Competitive inhibitors; Hit-to-probe optimization; SMOOTH-MUSCLE CELLS; CALCIFICATION; BINDING;

D O I：

10.1016/j.bmcl.2008.10.107

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：222 / 225

页数：4

共 12 条

[11] BETA-GLYCEROPHOSPHATE ACCELERATES CALCIFICATION IN CULTURED BOVINE VASCULAR SMOOTH-MUSCLE CELLS
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Nishizawa, Y
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