Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore. Academic Article uri icon


  • 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.

published proceedings

  • J Med Chem

author list (cited authors)

  • Marino, J. P., Fisher, P. W., Hofmann, G. A., Kirkpatrick, R. B., Janson, C. A., Johnson, R. K., ... Thompson, S. K.

citation count

  • 55

complete list of authors

  • Marino, Joseph P||Fisher, Paul W||Hofmann, Glenn A||Kirkpatrick, Robert B||Janson, Cheryl A||Johnson, Randall K||Ma, Chun||Mattern, Michael||Meek, Thomas D||Ryan, M Dominic||Schulz, Christina||Smith, Ward W||Tew, David G||Tomazek, Thaddeus A||Veber, Daniel F||Xiong, Wenfang C||Yamamoto, Yuuichi||Yamashita, Keizo||Yang, Guang||Thompson, Scott K

publication date

  • August 2007