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首页> 外文期刊>Journal of Medicinal Chemistry >AMP deaminase inhibitors. 4. Further N3-substituted coformycin aglycon analogues: N3-alkylmalonates as ribose 5'-monophosphate mimetics.
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AMP deaminase inhibitors. 4. Further N3-substituted coformycin aglycon analogues: N3-alkylmalonates as ribose 5'-monophosphate mimetics.

机译：AMP脱氨酶抑制剂。 4.其他N 3-取代的甲酰辅酶A糖苷配基类似物：N 3-烷基丙二酸酯作为核糖5'-单磷酸酯模拟物。

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摘要

AMP deaminase (AMPDA) inhibitors increase the levels of extracellular adenosine and preserve intracellular adenylate pools in cellular models of ATP depletion and therefore represent a potential new class of antiischemic drugs. Recently we reported that replacement of the ribose 5'-monophosphate component of the very potent transition-state analogue AMPDA inhibitor coformycin monophosphate (1) with a simple alkylcarboxy group resulted in potent, selective, and cell-penetrating AMPDA inhibitors. Here we report that replacement of this alkylcarboxy group with an alpha-substituted alkylmalonic acid resulted in enhanced inhibitor potency. The lead compound, 3-(5, 5-dicarboxy-6-(3-(trifluoromethyl)phenyl)-n-hexyl)coformycin aglycon (21), exhibited an AMPDA K(i) of 0.029 &mgr;M which is (3 x 10(5))-fold lower than the K(M) for the natural substrate AMP. A comparison of inhibitory potencies shows that the diacid analogues with alpha-benzyl substituents are 2-10-fold more inhibitory than similar monoacid-monoester, monoester-monoamide, or diester derivatives. Finally, these diacid analogues are 2-40-fold more potent inhibitors than the corresponding monocarboxylates.
机译：AMP脱氨酶（AMPDA）抑制剂可在ATP耗竭的细胞模型中增加细胞外腺苷的水平并保留细胞内腺苷酸库，因此代表了潜在的一类新型抗缺血药物。最近，我们报道了用简单的烷基羧基取代非常有效的过渡态类似物AMPDA抑制剂单磷酸甲酰菌素（1）的核糖5'-单磷酸酯成分会产生有效，选择性和穿透细胞的AMPDA抑制剂。在这里，我们报道用α-取代的烷基丙二酸代替该烷基羧基导致增强的抑制剂效力。铅化合物3-（5,5-二羧基-6-（3-（三氟甲基）苯基）-正己基）可可霉素糖苷配基（21）的AMPDA K（i）为0.029 mg.M，为（3比天然底物AMP的K（M）低10倍（5））倍。抑制能力的比较显示，具有α-苄基取代基的二酸类似物的抑制作用比类似的单酸-单酯，单酯-单酰胺或二酯衍生物高2-10倍。最后，这些二酸类似物是比相应的单羧酸盐强2-40倍的有效抑制剂。

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