(2S)-2-[[(2S)-3-[3-[(3,5-dichlorophenyl)methyl]imidazol-4-yl]-1-hydroxy-1-oxopropan-2-yl]amino]-4-methylpentanoic acid | 305335-31-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S)-2-[[(2S)-3-[3-[(3,5-dichlorophenyl)methyl]imidazol-4-yl]-1-hydroxy-1-oxopropan-2-yl]amino]-4-methylpentanoic acid
• 英文别名: (2S)-2-[[(1S)-1-carboxy-2-[3-[(3,5-dichlorophenyl)methyl]imidazol-4-yl]ethyl]amino]-4-methylpentanoic acid；(S,S)-2-[1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl]-ethylamino]-4-methylpentanoic acid；(S,S)-2-{1-carboxy-2-[3-(3,5-dchlorobenzyl)-3H-imdazol-4-yl]ethylamno}-4-methylpentanoic acid；MLN-4760；MLN-4760-S；MLN 4760；(S,S)-2-{1-Carboxy-2-[3-(3,5-dichloro-benzyl)-3H-imidazol-4-YL]-ethylamino}-4-methyl-pentanoic acid
• CAS: 305335-31-3
• 化学式: C₁₉H₂₃Cl₂N₃O₄
• 分子量: 428.315
• InChiKey: NTCCRGGIJNDEAB-IRXDYDNUSA-N

物化性质

• 溶解度：
  可溶于DMSO

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  28
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  104
• 氢给体数：
  3
• 氢受体数：
  6

制备方法与用途

生物活性

MLN-4760（化合物16）是一种有效的、选择性的人血管紧张素转换酶2 (ACE2) 抑制剂，IC50值为0.44 nM。它还抑制牛羧肽酶A (CPDA)，其IC50值为27 μM。

靶点

Target	Value
ACE2	0.44 nM
CPDA	27 μM

体外研究

MLN-4760是一种强效且选择性的人ACE2抑制剂（IC50, 0.44 nM），相对于相关酶人睾丸ACE（IC50, >100 μM）和牛羧肽酶A (CPDA; IC50, 27 μM) 具有出色的特异性 (>5000倍)。MLN-4760有效地抑制了重组ACE2的切割，pIC50值为8.5±0.1，在rhACE2中的pIC50值为4.7±0.1、6.9±0.1，在小鼠心肌和单核细胞(MNCs) 中分别为4.4±0.1、6.2±0.1。

体内研究

MLN-4760（100 μM，连续五天脑室内灌注）在中风后4小时和3天内显著恶化神经功能，但并未显著增加梗死体积。

反应信息

• 作为产物：
  描述：

  3,5-二氯苯甲醇 在 盐酸 、 sodium hydroxide 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 25.5h， 生成 (2S)-2-[[(2S)-3-[3-[(3,5-dichlorophenyl)methyl]imidazol-4-yl]-1-hydroxy-1-oxopropan-2-yl]amino]-4-methylpentanoic acid
  参考文献：
  名称：

  Substrate-Based Design of the First Class of Angiotensin-Converting Enzyme-Related Carboxypeptidase (ACE2) Inhibitors

  摘要：

  Angiotensin-converting enzyme-related carboxypeptidase (ACE2) is a recently identified zinc metalloprotease with carboxypeptidase activity that was identified using our genomics platform. We implemented a rational design approach to identify potent and selective ACE2 inhibitors. To this end, picomolar inhibitors of ACE2 were designed and synthesized.

  DOI：

  10.1021/ja0277226

文献信息

• ACE-2 modulating compounds and methods of use thereof
  申请人：——

  公开号：US20040082496A1

  公开（公告）日：2004-04-29

  ACE-2 modulating compounds for the treatment of body weight disorders are disclosed. Methods of using the compounds and pharmaceutical compositions containing the compounds are also claimed.

  抗ACE-2调节化合物用于治疗体重失调的方法已被披露。还声称了使用这些化合物的方法和含有这些化合物的药物组合物。
• NOVEL SALTS, POLYMORPHS, AND SYNTHETIC PROCESSES REGARDING IMIDAZOLE DERIVATIVE
  申请人：Partridge John Joseph

  公开号：US20110319461A1

  公开（公告）日：2011-12-29

  The present invention relates to a process for producing 2-[1-(S)-carboxy-2(S)-[3-(3,5-dichloro-benzyl)-3H-imidazol-4-yl]-ethylamino]-4-methyl-pentanoic acid, as well as novel salts, including hydrates and solvates thereof, and novel crystalline and amorphous forms thereof.

  本发明涉及一种生产2-[1-(S)-羧基-2(S)-[3-(3,5-二氯苄基)-3H-咪唑-4-基]-乙基氨基]-4-甲基-戊酸的方法，以及其新型盐，包括水合物和溶剂化合物，以及其新型晶体和非晶形式。
• Methods for modulating pigmentation by angiotensin-converting enzyme 2 modulation
  申请人：Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft

  公开号：US11337909B2

  公开（公告）日：2022-05-24

  A cosmetic method for modulating pigmentation in a subject includes administering a modulator of angiotensin-converting enzyme 2 (ACE2 modulator) to the subject. The ACE2 modulator can be an inhibitor of angiotensin-converting enzyme 2 (ACE2 inhibitor), in which case, the ACE2 inhibitor can be administered to increase pigmentation in the subject. The ACE2 modulator can also be an activator of angiotensin-converting enzyme 2 (ACE2 activator), in which case the ACE2 activator can be administered to decrease pigmentation in the subject. The treatment of inflammatory skin disease can also be achieved by inhibition of angiotensin-converting enzyme 2.

  一种调节受试者色素沉着的美容方法包括向受试者施用血管紧张素转化酶 2 的调节剂（ACE2 调节剂）。ACE2 调节剂可以是血管紧张素转换酶 2 的抑制剂（ACE2 抑制剂），在这种情况下，可以施用 ACE2 抑制剂来增加受试者的色素沉着。ACE2 调节剂也可以是血管紧张素转化酶 2 的激活剂（ACE2 激活剂），在这种情况下，可以使用 ACE2 激活剂来减少受试者的色素沉着。还可以通过抑制血管紧张素转化酶 2 来治疗炎症性皮肤病。
• Crystal structure of angiotensin-converting enzyme-related carboxypeptidase
  申请人：——

  公开号：US20040209344A1

  公开（公告）日：2004-10-21

  The invention relates to molecules or molecular complexes which comprise binding pockets of angiotensin-converting enzyme-related carboxypeptidase or its homologues. The invention relates to a computer comprising a data storage medium encoded with the structure coordinates of such binding pockets. The invention also relates to methods of using the structure coordinates to solve the structure of homologous proteins or protein complexes. The invention relates to methods of using the structure coordinates to screen for and design compounds that bind to angiotensin-converting enzyme-related carboxypeptidase protein or homologues thereof. The invention also relates to crystallizable compositions and crystals comprising angiotensin-converting enzyme-related carboxypeptidase protein or angiotensin-converting enzyme-related carboxypeptidase protein complexes.

  本发明涉及包含血管紧张素转换酶相关羧肽酶或其同源物结合口袋的分子或分子复合物。本发明涉及一种计算机，该计算机包含一个数据存储介质，该介质编码有此类结合口袋的结构坐标。本发明还涉及使用这些结构坐标求解同源蛋白质或蛋白质复合物结构的方法。本发明涉及利用结构坐标筛选和设计与血管紧张素转换酶相关羧肽酶蛋白或其同源物结合的化合物的方法。本发明还涉及包含血管紧张素转换酶相关羧肽酶蛋白或血管紧张素转换酶相关羧肽酶蛋白复合物的可结晶组合物和晶体。
• Substrate-Based Design of the First Class of Angiotensin-Converting Enzyme-Related Carboxypeptidase (ACE2) Inhibitors
  作者：Natalie A. Dales、Alexandra E. Gould、James A. Brown、Emily F. Calderwood、Bing Guan、Charles A. Minor、James M. Gavin、Paul Hales、Virendar K. Kaushik、Michael Stewart、Peter J. Tummino、Chad S. Vickers、Timothy D. Ocain、Michael A. Patane

  DOI：10.1021/ja0277226

  日期：2002.10.1

  Angiotensin-converting enzyme-related carboxypeptidase (ACE2) is a recently identified zinc metalloprotease with carboxypeptidase activity that was identified using our genomics platform. We implemented a rational design approach to identify potent and selective ACE2 inhibitors. To this end, picomolar inhibitors of ACE2 were designed and synthesized.