文摘
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 andinterative synthesis of triazoles led to rapid SAR development around the aniline, benzylthio, and triazolemoeities. Evaluation of these analogs in a human MetAP2 enzyme assay led to the identification of severalinhibitors with potencies in the 50-100 picomolar range. The deleterious effects on inhibitor potency bymethylation of the anilino-triazole nitrogens, as well as the X-ray crystal structure of triazole 102 bound inthe active site of MetAP2, confirm the key interactions between the triazole nitrogens, the active site cobaltatoms, and the His-231 side-chain. The structure has also provided a rationale for interpreting SAR withinthe triazole series. Key aniline (2-isopropylphenyl) and sulfur substituents (furanylmethyl) identified in theSAR 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 angiogenesishighlighting the potential utility of MetAP2 inhibitors as anticancer agents.