Nucleoside-5′-monophosphates as Prodrugs of Adenosine A2A Receptor Agonists Activated by ecto-5′-Nucleotidase
Nucleoside-5′-monophosphates as Prodrugs of Adenosine A2A Receptor Agonists Activated by ecto-5′-Nucleotidase
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DOI：
10.1021/jm900538v
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发表时间：
2009-12-10
影响因子：
7.3
通讯作者：
Mueller, Christa E.
中科院分区：
文献类型：
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作者：
El-Tayeb, Ali;Iqbal, Jamshed;Mueller, Christa E.
腺苷A(2A)受体激动剂的前体药物可被胞外-5‘-核苷酸酶(ecto-5’-NT，CD73)激活。由于ecto-5‘-NT在炎症组织中表达上调，A(2A)激动剂有望在炎症部位以前药的形式释放。合成并研究了2-(Ar)烷基取代的AMP衍生物。某些2-取代的AMP衍生物，包括2-己基硫代-AMP、2-环戊基硫代-AMP、2-环己基甲基硫代-AMP和2-环己基乙基硫代-AMP可以被ecto-5‘-NT接受，并容易转化为相应的2-取代腺苷衍生物。2-环己基乙硫基取代是ECTO-5‘-NT和腺苷A(2A)受体要求之间的一个很好的折衷。相应的AMP衍生物(12G)是与AMP本身类似的良好底物，而得到的腺苷衍生物(11G)是相对有效的A(2A)激动剂(与大鼠脑纹状体膜结合的放射性配体：K-I=372 nM；抑制抗CD3/抗CD28诱导的小鼠CD4+细胞干扰素-γ的释放：EC50=50 nM)。化合物11g通过与从野生型小鼠分离的CD4+细胞孵育而从12g中释放，但从ecto-5‘-nt基因敲除小鼠的细胞中释放的程度要小得多。化合物12G将成为一种新的先导结构，用于开发更有效、更选择性的选择性抗炎A(2A)受体激动剂的ecto-5‘-NT激活前药。
Prodrugs of adenosine A(2A) receptor agonists were developed that are activated by ecto-5'-nucleotidase (ecto-5'-NT, CD73). Because ecto-5'-NT is upregulated in inflamed tissue, the A(2A) agonists are expected to be released from their prodrug form at the sites of inflammation. 2-(Ar)alkyl-substituted AMP derivatives were synthesized and investigated. Certain 2-substituted AMP derivatives, including 2-hexylthio-AMP, 2-cyclopentylthio-AMP, 2-cyclohexylmethylthio-AMP, and 2-cyclohexylethylthio-AMP were accepted as substrates by ecto-5'-NT and readily converted to the corresponding 2-substituted adenosine derivatives. The 2-cyclohexylethylthio substitution was a good compromise between the requirements of the ecto-5'-NT and the adenosine A(2A) receptor. The corresponding AMP derivative (12g) was a similarly good substrate as AMP itself, while the resulting adenosine derivative (11g) was a relatively potent A(2A) agonist (radioligand binding to rat brain striatal membranes: K-i = 372 nM; inhibition of anti-CD3/anti-CD28-induced IFN-gamma release in mouse CD4+ cells: EC50 = 50 nM). Compound 11g was released from 12g by incubation with CD4+ cells isolated from wild-type mice but only to a much smaller extent by cells from ecto-5'-NT knockout mice. Compound 12g will be a new lead structure for the development of more potent and selective ecto-5'-NT-activated prodrugs of selective anti-inflammatory A(2A) receptor agonists.