Highly Potent Inhibitors of Methionine Aminopeptidase-2 Based on a 1,2,4-Triazole Pharmacophore

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• 作者：Joseph P. Marino ; Jr. ; Paul W. Fisher ; Glenn A. Hofmann ; Robert B. Kirkpatrick ; Cheryl A. Janson ; Randall K. Johnson ; Chun Ma ; Michael Mattern ; Thomas D. Meek ; M. Dominic Ryan ; Christina Schulz ; Ward
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：August 9, 2007
• 年：2007
• 卷：50
• 期：16
• 页码：3777 - 3785
• 全文大小：165K
• 年卷期：v.50,no.16(August 9, 2007)
• ISSN：1520-4804

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.