2. Academic Validation
  3. 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

  • J Med Chem. 2007 Aug 9;50(16):3777-85. doi: 10.1021/jm061182w.
Joseph P Marino Jr 1,  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 W Smith,  David G Tew,  Thaddeus A Tomazek Jr,  Daniel F Veber,  Wenfang C Xiong,  Yuuichi Yamamoto,  Keizo Yamashita,  Guang Yang,  Scott K Thompson
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Enzymology, Oncology, and Structural Biology, GlaxoSmithkline, King of Prussia, PA 19406, USA. joseph.p.marino@gsk.com
PMID: 17636946 DOI: 10.1021/jm061182w
Abstract

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.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z