N-(3,4,5-trifluorobenzyl)-(S)-3-hydroxy-2-oxo-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrrolidine-3-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: N-(3,4,5-trifluorobenzyl)-(S)-3-hydroxy-2-oxo-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrrolidine-3-carboxamide
• 英文别名: (S)-3-hydroxy-2-oxo-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrrolidine-3-carboxylic acid 3,4,5-trifluorobenzylamide；(3S)-3-hydroxy-2-oxo-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-N-[(3,4,5-trifluorophenyl)methyl]pyrrolidine-3-carboxamide
• 化学式: C₂₁H₁₈F₃N₃O₄
• 分子量: 433.387
• InChiKey: AJIOJGRRRWENCI-NRFANRHFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  98.7
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  6-氨基-3,4-二氢-2(1H)-喹啉酮 在 N-甲基吗啉 、 盐酸 、 magnesium bis(monoperoxyphthalate)hexahydrate 、 水 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 sodium hydroxide 作用下， 以 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 28.0h， 生成 N-(3,4,5-trifluorobenzyl)-(S)-3-hydroxy-2-oxo-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrrolidine-3-carboxamide
  参考文献：
  名称：

  Identification of Methionine Aminopeptidase-2 (MetAP-2) Inhibitor M8891: A Clinical Compound for the Treatment of Cancer

  摘要：

  The recently disclosed next generation of reversible, selective, and potent MetAP-2 inhibitors introduced a cyclic tartronic diamide scaffold. However, the lead compound la suffered from enterohepatic circulation, preventing further development. Nevertheless, la served as a starting point for further optimization. Maintaining potent antiproliferation activity, while improving other compound properties, enabled the generation of an attractive array of new MetAP-2 inhibitors. The most promising derivatives were identified by a multiparameter analysis of the compound properties. Essential for the efficient selection of candidates with in vivo activity was the identification of molecules with a long residence time on the target protein, high permeability, and low efflux ratio not only in Caco-2 but also in the MDR-MDCK cell line. Orally bioavailable, potent, and reversible MetAP-2 inhibitors impede the growth of primary endothelial cells and demonstrated antitumoral activity in mouse models. This assessment led to the nomination of the clinical development compound M8891, which is currently in phase I clinical testing in oncology patients.

  DOI：

  10.1021/acs.jmedchem.9b01070

文献信息

• CYCLIC AMIDES AS METAP-2 INHIBITORS
  申请人：MERCK PATENT GmbH

  公开号：US20150031670A1

  公开（公告）日：2015-01-29

  Compounds of the formula (I), in which R 1 , R 3 , R 5 , R 6 , R 7 , R, X and Y have the meanings indicated in Claim 1 , are inhibitors of methionine aminopeptidase and can be employed for the treatment of tumours.

  式(I)中的化合物，其中R1、R3、R5、R6、R7、R、X和Y具有权利要求1中指示的含义，是蛋氨酸氨基肽酶的抑制剂，可用于肿瘤的治疗。
• Cyclic amides as MetAP-2 inhibitors
  申请人：MERCK PATENT GmbH

  公开号：US10093623B2

  公开（公告）日：2018-10-09

  Described are cyclic amide compounds of the formula (I): in which R1, R3, R5, R6, R7, R, X and Y have the meanings as described. The compounds are inhibitors of methionine aminopeptidase and can be employed for the treatment of tumors.

  所述的是式 (I) 的环状酰胺化合物： 其中 R1、R3、R5、R6、R7、R、X 和 Y 的含义如前所述。这些化合物是蛋氨酸氨肽酶的抑制剂，可用于治疗肿瘤。
• CYCLISCHE AMIDE ALS METAP-2 INHIBITOREN
  申请人：Merck Patent GmbH

  公开号：EP2834221B1

  公开（公告）日：2016-05-25
• [DE] CYCLISCHE AMIDE ALS METAP-2 INHIBITOREN<br/>[EN] CYCLIC AMIDES AS METAP-2 INHIBITORS<br/>[FR] AMIDES CYCLIQUES COMME INHIBITEURS DE METAP-2
  申请人：MERCK PATENT GMBH

  公开号：WO2013149704A1

  公开（公告）日：2013-10-10

  Verbindungen der Formel (I) worin R1, R3, R5, R6, R7, R, X und Y die in Anspruch 1 angegebenen Bedeutungen haben, sind Inhibitoren der Methionin-Amino-Peptidase und können zur Behandlung von Tumoren eingesetzt werden.
• Identification of Methionine Aminopeptidase-2 (MetAP-2) Inhibitor <b>M8891</b>: A Clinical Compound for the Treatment of Cancer
  作者：Timo Heinrich、Jeyaprakashnarayanan Seenisamy、Frank Becker、Beatrix Blume、Jörg Bomke、Melanie Dietz、Uwe Eckert、Manja Friese-Hamim、Jakub Gunera、Kerrin Hansen、Birgitta Leuthner、Djordje Musil、Jens Pfalzgraf、Felix Rohdich、Christian Siegl、Dieter Spuck、Ansgar Wegener、Frank T. Zenke

  DOI：10.1021/acs.jmedchem.9b01070

  日期：2019.12.26

  The recently disclosed next generation of reversible, selective, and potent MetAP-2 inhibitors introduced a cyclic tartronic diamide scaffold. However, the lead compound la suffered from enterohepatic circulation, preventing further development. Nevertheless, la served as a starting point for further optimization. Maintaining potent antiproliferation activity, while improving other compound properties, enabled the generation of an attractive array of new MetAP-2 inhibitors. The most promising derivatives were identified by a multiparameter analysis of the compound properties. Essential for the efficient selection of candidates with in vivo activity was the identification of molecules with a long residence time on the target protein, high permeability, and low efflux ratio not only in Caco-2 but also in the MDR-MDCK cell line. Orally bioavailable, potent, and reversible MetAP-2 inhibitors impede the growth of primary endothelial cells and demonstrated antitumoral activity in mouse models. This assessment led to the nomination of the clinical development compound M8891, which is currently in phase I clinical testing in oncology patients.