(S)-2-(2,6-dichloro-benzoylamino)-3-(4-boronophenyl)-propionic acid | 863228-94-8

• 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: (S)-2-(2,6-dichloro-benzoylamino)-3-(4-boronophenyl)-propionic acid
• 英文别名: (S)-3-(4-boronophenyl)-2-(2,6-dichlorobenzamido)propanoic acid；(2S)-3-(4-boronophenyl)-2-[(2,6-dichlorobenzoyl)amino]propanoic acid
• CAS: 863228-94-8
• 化学式: C₁₆H₁₄BCl₂NO₅
• 分子量: 382.008
• InChiKey: FBGWCIMABLLKTJ-ZDUSSCGKSA-N

物化性质

• 密度：
  1.50±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  107
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-2-(2,6-dichloro-benzoylamino)-3-(4-boronophenyl)-propionic acid 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium 、 sodium carbonate 作用下， 以 乙腈 为溶剂， 反应 2.17h， 生成 (2S)-2-[(2,6-dichlorophenyl)formamido]-3-{4-[5-(2-hydroxyethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl]phenyl}propanoic acid
  参考文献：
  名称：

  Synthesis and Biological Evaluation of Novel Pyridazinone-Based α₄ Integrin Receptor Antagonists

  摘要：

  A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha(4)beta(1)/VCAM-1 and alpha(4)beta(7)/MAdCAM-1 interactions. Concise syntheses were developed and applied for exploration of structure-activity relationships pertaining to the pyridazinone ring as well as the N-acyl phenylalanine scaffold. Potent dual antagonists of alpha(4)beta(1) and alpha(4)beta(7) were generated from an amide subseries; antagonists selective for alpha(4)beta(7) were identified from urea and carbamate-based subseries. The pharmacokinetic properties of selected members of the series have been determined in rats and demonstrate that the use of ester prodrugs and alterations to the amide linkage can lead to improved oral bioavailability in this series. An alpha(4),beta(7)-selective member of the carbamate subseries (36c), upon oral admininstration, demonstrated in vivo efficacy in the mouse DSS colitis model.

  DOI：

  10.1021/jm060031q
• 作为产物：
  描述：

  4-硼-L-苯丙氨酸 、 2,6-二氯苯甲酰氯 在 sodium carbonate 作用下， 以 乙腈 为溶剂， 生成 (S)-2-(2,6-dichloro-benzoylamino)-3-(4-boronophenyl)-propionic acid
  参考文献：
  名称：

  非RGDα4β1拮抗剂衍生的有效，选择性和类似药物的RGDαvβ1小分子抑制剂的设计。

  摘要：

  在发达国家，多达45％的死亡可归因于慢性纤维增生性疾病，这凸显了对有效疗法的需求。最近研究了RGD（Arg-Gly-Asp）整联蛋白αvβ1在纤维化疾病中的作用，因此值得治疗靶向。在本文中，我们描述了非RGD命中的小分子αvβ1抑制剂的鉴定。我们表明，αvβ1的活性嵌入了一系列已发布的α4β1（VLA-4）配体中。我们还展示了如何将非RGD整联蛋白抑制剂（在这种情况下为α4β1）转化为有效的非两性离子RGD整联蛋白抑制剂（在这种情况下为αvβ1）。我们设计了对α4β1和其他αv整联蛋白（αvβ3，αvβ5，αvβ6，αvβ8）具有优异选择性的脲配体。在计算机对接模型和密度泛函理论（DFT）计算的帮助下，发现了尿素铅系列。

  DOI：

  10.1002/cmdc.201900359

文献信息

• Pyridazinones as antagonists of alpha4 integrins
  申请人：Barbay Kent

  公开号：US20050192279A1

  公开（公告）日：2005-09-01

  The present invention relates to certain novel compounds of Formula (I): methods for preparing these compounds, compositions, intermediates and derivatives thereof and for the treatment of integrin mediated disorders.

  本发明涉及某些化合物的新颖结构，其化学式为（I）：制备这些化合物的方法，组合物，中间体及其衍生物以及用于治疗整合素介导的疾病。
• Synthesis and SAR of pyridazinone-substituted phenylalanine amide α4 integrin antagonists
  作者：Yong Gong、J. Kent Barbay、Edward S. Kimball、Rosemary J. Santulli、M. Carolyn Fisher、Alexey B. Dyatkin、Tamara A. Miskowski、Pamela J. Hornby、Wei He

  DOI：10.1016/j.bmcl.2008.01.022

  日期：2008.2

  Structural modi. cation and cellular adhesion inhibition activities of pyridazinone-substituted phenylalanine amide alpha(4) integrin antagonists are described. Functionality requirements for the arylamide moiety and the carboxylic acid group were demonstrated. The study also revealed novel structure - activity relationships (SAR) for arylated pyridazinones. A correlation between bioavailability and permeability was also explored. A selected compound showed effectiveness in a mouse leukocytosis study. (c) 2008 Elsevier Ltd. All rights reserved.
• Synthesis and Biological Evaluation of Novel Pyridazinone-Based α₄ Integrin Receptor Antagonists
  作者：Yong Gong、J. Kent Barbay、Alexey B. Dyatkin、Tamara A. Miskowski、Edward S. Kimball、Stephen M. Prouty、M. Carolyn Fisher、Rosemary J. Santulli、Craig R. Schneider、Nathaniel H. Wallace、Scott A. Ballentine、William E. Hageman、John A. Masucci、Bruce E. Maryanoff、Bruce P. Damiano、Patricia Andrade-Gordon、Dennis J. Hlasta、Pamela J. Hornby、Wei He

  DOI：10.1021/jm060031q

  日期：2006.6.1

  A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha(4)beta(1)/VCAM-1 and alpha(4)beta(7)/MAdCAM-1 interactions. Concise syntheses were developed and applied for exploration of structure-activity relationships pertaining to the pyridazinone ring as well as the N-acyl phenylalanine scaffold. Potent dual antagonists of alpha(4)beta(1) and alpha(4)beta(7) were generated from an amide subseries; antagonists selective for alpha(4)beta(7) were identified from urea and carbamate-based subseries. The pharmacokinetic properties of selected members of the series have been determined in rats and demonstrate that the use of ester prodrugs and alterations to the amide linkage can lead to improved oral bioavailability in this series. An alpha(4),beta(7)-selective member of the carbamate subseries (36c), upon oral admininstration, demonstrated in vivo efficacy in the mouse DSS colitis model.
• The Design of Potent, Selective and Drug‐Like RGD αvβ1 Small‐Molecule Inhibitors Derived from non‐RGD α4β1 Antagonists
  作者：Richard J. D. Hatley、Tim N. Barrett、Robert J. Slack、Morag E. Watson、Daniel J. Baillache、Anna Gruszka、Yoshiaki Washio、James E. Rowedder、Peter Pogány、Sandeep Pal、Simon J. F. Macdonald

  DOI：10.1002/cmdc.201900359

  日期：2019.7.17

  effective therapies. The RGD (Arg‐Gly‐Asp) integrin αvβ1 was recently investigated for its role in fibrotic disease, and thus warrants therapeutic targeting. Herein we describe the identification of non‐RGD hit small‐molecule αvβ1 inhibitors. We show that αvβ1 activity is embedded in a range of published α4β1 (VLA‐4) ligands; we also demonstrate how a non‐RGD integrin inhibitor (of α4β1 in this case) was

  在发达国家，多达45％的死亡可归因于慢性纤维增生性疾病，这凸显了对有效疗法的需求。最近研究了RGD（Arg-Gly-Asp）整联蛋白αvβ1在纤维化疾病中的作用，因此值得治疗靶向。在本文中，我们描述了非RGD命中的小分子αvβ1抑制剂的鉴定。我们表明，αvβ1的活性嵌入了一系列已发布的α4β1（VLA-4）配体中。我们还展示了如何将非RGD整联蛋白抑制剂（在这种情况下为α4β1）转化为有效的非两性离子RGD整联蛋白抑制剂（在这种情况下为αvβ1）。我们设计了对α4β1和其他αv整联蛋白（αvβ3，αvβ5，αvβ6，αvβ8）具有优异选择性的脲配体。在计算机对接模型和密度泛函理论（DFT）计算的帮助下，发现了尿素铅系列。