(S)-3-hydroxy-2-oxo-1-phenylpyrrolidine-3-carboxylic acid (4-methylthiophen-2-ylmethyl)amide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (S)-3-hydroxy-2-oxo-1-phenylpyrrolidine-3-carboxylic acid (4-methylthiophen-2-ylmethyl)amide
• 英文别名: (3S)-3-hydroxy-N-[(4-methylthiophen-2-yl)methyl]-2-oxo-1-phenylpyrrolidine-3-carboxamide
• 化学式: C₁₇H₁₈N₂O₃S
• 分子量: 330.408
• InChiKey: ANPHNJXCKYCPNS-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  97.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  1-苯基-2-氧-3-吡咯烷羧酸 在 氯化亚砜 、 lithium hydroxide monohydrate 、 cerium(III) chloride heptahydrate 、 氧气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 正己烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.33h， 生成 (S)-3-hydroxy-2-oxo-1-phenylpyrrolidine-3-carboxylic acid (4-methylthiophen-2-ylmethyl)amide
  参考文献：
  名称：

  Discovery and Structure-Based Optimization of Next-Generation Reversible Methionine Aminopeptidase-2 (MetAP-2) Inhibitors

  摘要：

  Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process, and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the lipophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from HTS campaign I la was discovered with an enzymatic IC50 of 150 nM. The resynthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC50 of 1.9 mu M. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC50 of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and antitumor efficacy which led to the identification of advanced lead 21.

  DOI：

  10.1021/acs.jmedchem.9b00041

文献信息

• PYRROLIDINONES AS METAP-2 INHIBITORS
  申请人：Heinrich Timo

  公开号：US20130296274A1

  公开（公告）日：2013-11-07

  Compounds of the formula I in which R 1 , R 2 , R 3 and R 4 have the meanings indicated in Claim 1 , are inhibitors of methionine aminopeptidase and can be employed for the treatment of tumours.

  公式I中，R1、R2、R3和R4的含义如权利要求1所示的化合物是蛋氨酸氨肽酶的抑制剂，可用于治疗肿瘤。
• PYRROLIDINONE ALS METAP-2 INHIBITOREN
  申请人：Merck Patent GmbH

  公开号：EP2627631B1

  公开（公告）日：2015-12-16
• US8895535B2
  申请人：——

  公开号：US8895535B2

  公开（公告）日：2014-11-25
• Discovery and Structure-Based Optimization of Next-Generation Reversible Methionine Aminopeptidase-2 (MetAP-2) Inhibitors
  作者：Timo Heinrich、Jeyaprakashnarayanan Seenisamy、Beatrix Blume、Jörg Bomke、Michel Calderini、Uwe Eckert、Manja Friese-Hamim、Rainer Kohl、Martin Lehmann、Birgitta Leuthner、Djordje Musil、Felix Rohdich、Frank T. Zenke

  DOI：10.1021/acs.jmedchem.9b00041

  日期：2019.5.23

  Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process, and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the lipophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from HTS campaign I la was discovered with an enzymatic IC50 of 150 nM. The resynthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC50 of 1.9 mu M. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC50 of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and antitumor efficacy which led to the identification of advanced lead 21.