Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore
Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore
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DOI：
10.1021/jm061182w
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发表时间：
2007-08-09
影响因子：
7.3
通讯作者：
Thompson, Scott K.
中科院分区：
文献类型：
--
作者：
Marino, Joseph P., Jr.;Fisher, Paul W.;Thompson, Scott K.
高通量筛选人金属蛋白酶甲硫氨酸氨基肽酶-2 （MetAP2）抑制剂，鉴定出一类有效的3-苯胺-5-苄基硫-1,2,4-三唑化合物。高效的排列和三唑的相互合成使得围绕苯胺、苄基硫和三唑基团的合成孔径雷达迅速发展。这些类似物在人MetAP2酶分析中的评估导致鉴定出几种抑制剂，其效力在50-100皮摩尔范围内。苯胺-三唑氮甲基化对抑制剂效力的有害影响，以及结合在MetAP2活性位点的三唑102的x射线晶体结构，证实了三唑氮、活性位点钴原子和His-231侧链之间的关键相互作用。该结构也为解释三唑系列的SAR提供了理论依据。在SAR研究中发现的关键苯胺（2-异丙基苯基）和硫取代基（呋喃基甲基）导致内皮细胞增殖的有效抑制剂（103和104）的鉴定。三唑103和三唑104在血管生成的主动脉环组织模型中也表现出剂量依赖的活性，这突出了MetAP2抑制剂作为抗癌药物的潜在效用。
High-throughput screening for inhibitors of the human metalloprotease, methionine aminopeptidase-2 (MetAP2), identified a potent class of 3-anilino-5-benzylthio-1,2,4-triazole compounds. Efficient array and interative synthesis of triazoles led to rapid SAR development around the aniline, benzylthio, and triazole moeities. Evaluation of these analogs in a human MetAP2 enzyme assay led to the identification of several inhibitors with potencies in the 50-100 picomolar range. The deleterious effects on inhibitor potency by methylation of the anilino-triazole nitrogens, as well as the X-ray crystal structure of triazole 102 bound in the active site of MetAP2, confirm the key interactions between the triazole nitrogens, the active site cobalt atoms, and the His-231 side-chain. The structure has also provided a rationale for interpreting SAR within the triazole series. Key aniline (2-isopropylphenyl) and sulfur substituents (furanylmethyl) identified in the SAR studies led to the identification of potent inhibitors (103 and 104) of endothelial cell proliferation. Triazoles 103 and 104 also exhibited dose-dependent activity in an aortic ring tissue model of angiogenesis highlighting the potential utility of MetAP2 inhibitors as anticancer agents.