(3-amino-benzoylamino)-acetic acid methyl ester | 56445-69-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (3-amino-benzoylamino)-acetic acid methyl ester
• 英文别名: Methyl 2-[(3-aminophenyl)formamido]acetate；methyl 2-[(3-aminobenzoyl)amino]acetate
• CAS: 56445-69-3
• 化学式: C₁₀H₁₂N₂O₃
• mdl: MFCD09048615
• 分子量: 208.217
• InChiKey: KPFZCMGSPFSUAB-UHFFFAOYSA-N

物化性质

• 沸点：
  416.6±30.0 °C(Predicted)
• 密度：
  1.235±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  81.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (3-amino-benzoylamino)-acetic acid methyl ester 在 lithium hydroxide 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 (3-{2-[4-(3-o-Tolyl-ureido)-phenyl]-acetylamino}-benzoylamino)-acetic acid
  参考文献：
  名称：

  Identification of Potent and Novel α4β1 Antagonists Using in Silico Screening

  摘要：

  The antigen alpha4beta1 (very late antigen-4, VLA-4) plays an important role in the migration of white blood cells to sites of inflammation. It has been implicated in the pathology of a variety of diseases including asthma, multiple sclerosis, and rheumatoid arthritis. We describe a series of potent inhibitors of alpha4beta1 that were discovered using computational screening for replacements of the peptide region of an existing tetrapeptide-based alpha4beta1 inhibitor (1; 4-[N'-(2-methylphenyl)-ureido]phenylacetyl-Leu-Asp-Val) derived from fibronectin. The search query was constructed using a model of 1 that was based upon the X-ray conformation of the related integrin-binding region of vascular cell adhesion molecule-1 (VCAM-1). The 3D search query consisted of the N-terminal cap and the carboxyl side chain of 1 because, upon the basis of existing structure-activity data on this series, these were known to be critical for high-affinity binding to alpha4beta1. The computational screen identified 12 reagents from a virtual library of 8624 molecules as satisfying the model and our synthetic filters. All of the synthesized compounds tested inhibit alpha4beta1 association with VCAM-1, with the most potent compound having an IC50 of 1 nM, comparable to the starting compound. Using CATALYST, a 3D QSAR was generated that rationalizes the variation in activities of these alpha4beta1 antagonists. The most potent compound was evaluated in a sheep model of asthma, and a 30 mg nebulized dose was able to inhibit early and late airway responses in allergic sheep following antigen challenge and prevented the development of nonspecific airway hyperresponsiveness to carbachol. Our results demonstrate that it is possible to rapidly identify nonpeptidic replacements of integrin peptide antagonists, This approach should be useful in identification of nonpeptidic alpha4beta1 inhibitors with improved pharmacokinetic properties relative to their peptidic counterparts.

  DOI：

  10.1021/jm020054e
• 作为产物：
  描述：

  (3-nitro-benzoylamino)-acetic acid methyl ester 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 反应 14.0h， 生成 (3-amino-benzoylamino)-acetic acid methyl ester
  参考文献：
  名称：

  Identification of Potent and Novel α4β1 Antagonists Using in Silico Screening

  摘要：

  The antigen alpha4beta1 (very late antigen-4, VLA-4) plays an important role in the migration of white blood cells to sites of inflammation. It has been implicated in the pathology of a variety of diseases including asthma, multiple sclerosis, and rheumatoid arthritis. We describe a series of potent inhibitors of alpha4beta1 that were discovered using computational screening for replacements of the peptide region of an existing tetrapeptide-based alpha4beta1 inhibitor (1; 4-[N'-(2-methylphenyl)-ureido]phenylacetyl-Leu-Asp-Val) derived from fibronectin. The search query was constructed using a model of 1 that was based upon the X-ray conformation of the related integrin-binding region of vascular cell adhesion molecule-1 (VCAM-1). The 3D search query consisted of the N-terminal cap and the carboxyl side chain of 1 because, upon the basis of existing structure-activity data on this series, these were known to be critical for high-affinity binding to alpha4beta1. The computational screen identified 12 reagents from a virtual library of 8624 molecules as satisfying the model and our synthetic filters. All of the synthesized compounds tested inhibit alpha4beta1 association with VCAM-1, with the most potent compound having an IC50 of 1 nM, comparable to the starting compound. Using CATALYST, a 3D QSAR was generated that rationalizes the variation in activities of these alpha4beta1 antagonists. The most potent compound was evaluated in a sheep model of asthma, and a 30 mg nebulized dose was able to inhibit early and late airway responses in allergic sheep following antigen challenge and prevented the development of nonspecific airway hyperresponsiveness to carbachol. Our results demonstrate that it is possible to rapidly identify nonpeptidic replacements of integrin peptide antagonists, This approach should be useful in identification of nonpeptidic alpha4beta1 inhibitors with improved pharmacokinetic properties relative to their peptidic counterparts.

  DOI：

  10.1021/jm020054e

文献信息

• [EN] GASTRIN AND CHOLECYSTOKININ RECEPTOR LIGANDS<br/>[FR] LIGANDS DES RECEPTEURS DE LA GASTRINE ET DE LA CHOLECYSTOKININE
  申请人：BLACK JAMES FOUNDATION

  公开号：WO2000027823A1

  公开（公告）日：2000-05-18

  Compounds of formula (I) and their pharmaceutically acceptable salts are ligands at gastrin and/or cholecystokinin receptors. X and Y are independently =N-, -N(R5)- =CH-, -S- or -O-. n is from 1 to 4; R1 is H or C¿1? to C15 hydrocarbyl R?2¿ is selected from H, Me, Et, Pr and OH, R¿3? is selected from H, Me, Et and Pr; or (when n is greater than 1) each R?3¿ is independently selected from H, Me, Et and Pr, or two R3 groups on neighbouring carbon atoms are linked to form a C¿3? to C6 carbocylic ring, or R?2 and R3¿ on the same carbon atom together represent an =O group; R4 is C1 to C15 hydrocarbyl Z is -(NR7)a-CO-(NR8)b- (wherein a is 0 or 1, b is 0 or 1, -CO-NR7-CH2-CO-NR8-, -CO-O-, -CH¿2?-CH2-, -CH=CH-, -CH2-NR?8¿- or a bond; Q is -R9V, or (II), (wherein R9 is -CH¿2?-; -CH2-CH2-; or (III), R?9 and R8¿, together with the nitrogen atom to which R8 is attached, form a piperidine or pyrrolidine ring which is substituted by V; V is -CO-NH-SO¿2?-Ph, -SO2-NH-CO-Ph, -CH2OH, or a group of the formula -R?10¿U, (wherein U is -COOH, tetrazolyl, -CONHOH- or -SO¿3?H; and R?10¿ is a bond; C¿1? to C6 hydrocarbylene, -O-(C1 to C3 alkylene)-; -SO2NR?11-CHR12¿-; -CO-NR?11-CHR12¿-, or -NH-(CO)¿c?-CH2-, c being 0 or 1).

  式(I)化合物及其药学上可接受的盐是胃泌素和/或胆囊收缩素受体的配体。X和Y独立地为=N-，-N（R5）-，=CH-，-S-或-O-。n为1至4；R1为H或C1至C15的烃基；R2从H，Me，Et，Pr和OH中选择，R3从H，Me，Et和Pr中选择；或（当n大于1时）每个R3独立地从H，Me，Et和Pr中选择，或相邻碳原子上的两个R3基团连接形成C3至C6的环烷基，或R2和R3在同一碳原子上共同表示一个=O基团；R4为C1至C15的烃基，Z为-(NR7)a-CO-(NR8)b-（其中a为0或1，b为0或1，-CO-NR7-CH2-CO-NR8-，-CO-O-，-CH2-CH2-，-CH=CH-，-CH2-NR8-或键；Q为-R9V，或（II），（其中R9为-CH2-；-CH2-CH2-；或（III），R9和R8，连同R8所连接的氮原子，形成被V取代的哌嗪或吡咯烷环；V为-CO-NH-SO2-Ph，-SO2-NH-CO-Ph，-CH2OH，或式-R10U的基团（其中U为-COOH，四唑基，-CONHOH-或-SO3H；R10为键；C1至C6的烃亚基，-O-（C1至C3的烷基）-；-SO2NR11-CHR12-；-CO-NR11-CHR12-，或-NH-（CO）c-CH2-，其中c为0或1）。
• Gastrin and cholecystokinin receptor ligands
  申请人：James Black Foundation Limited

  公开号：US06479531B1

  公开（公告）日：2002-11-12

  Compounds of formula (I) and their pharmaceutically acceptable salts are ligands at gastrin and/or cholecystokinin receptors. X and Y are independently ═N—, —N(R5)—═CH—, —S— or —O—. n is from 1 to 4; R1 is H or C1 to C15 hydrocarbyl R2 is selected from H, Me, Et, Pr and OH, R3 is selected from H, Me, Et and Pr; or (when n is greater than 1) each R3 is independently selected from H, Me, Et and Pr, or two R3 groups on neighbouring carbon atoms are linked to form a C3 to C6 carbocylic ring, or R2 and R3 on the same carbon atom together represent an ═O group; R4 is C1 to C15 hydrocarbyl Z is —(NR7)a—CO—(NR8)b— (wherein a is 0 or 1, b is 0 or 1, —CO—NR7—CH2—CO—NR8—, —CO—O—, —CH2—CH2—, —CH═CH—, —CH2—NR8— or a bond; Q is —R9V, or (II), (wherein R9 is —CH2—; —CH2—CH2—; or (III), R9 and R8, together with the nitrogen atom to which R8 is attached, form a piperidine or pyrrolidine ring which is substituted by V; V is —CO—NH—SO2—Ph, —SO2—NH—CO—Ph, —CH2OH, or a group of the formula —R10U, (wherein U is —COOH, tetrazolyl, —CONHOH— or —SO3H; and R10 is a bond; C1 to C6 hydrocarbylene, —O—(C1 to C3 alkylene)—; —SO2NR11—CHR12—; —CO—NR11—CHR12—, or —NH—(CO)c—CH2—, c being 0 or 1).

  公式（I）的化合物及其药学上可接受的盐是胃泌素和/或胆囊收缩素受体的配体。X和Y分别是═N—，—N（R5）—═CH—，—S—或—O—。n为1到4；R1为H或C1到C15的烃基，R2从H、Me、Et、Pr和OH中选择，R3从H、Me、Et和Pr中选择；或（当n大于1时）每个R3独立地从H、Me、Et和Pr中选择，或相邻碳原子上的两个R3基团连接形成C3到C6的环烷基，或R2和同一碳原子上的R3一起代表═O基团；R4为C1到C15的烃基，Z为—（NR7）a—CO—（NR8）b—（其中a为0或1，b为0或1，—CO—NR7—CH2—CO—NR8—，—CO—O—，—CH2—CH2—，—CH═CH—，—CH2—NR8—或键；Q为—R9V，或（II），（其中R9为—CH2—；—CH2—CH2—；或（III），R9和R8与R8连接的氮原子一起形成被V取代的哌啶或吡咯烷环；V为—CO—NH—SO2—Ph，—SO2—NH—CO—Ph，—CH2OH，或公式—R10U的基团（其中U为—COOH、四唑基、—CONHOH—或—SO3H；R10为键；C1到C6的烃基亚甲基，—O—（C1到C3的亚甲基）—；—SO2NR11—CHR12—；—CO—NR11—CHR12—，或—NH—（CO）c—CH2—，其中c为0或1）。
• GASTRIN AND CHOLECYSTOKININ RECEPTOR LIGANDS
  申请人：JAMES BLACK FOUNDATION LIMITED

  公开号：EP1178969A1

  公开（公告）日：2002-02-13
• US6479531B1
  申请人：——

  公开号：US6479531B1

  公开（公告）日：2002-11-12
• Identification of Potent and Novel α4β1 Antagonists Using in Silico Screening
  作者：Juswinder Singh、Herman van Vlijmen、Yusheng Liao、Wen-Cherng Lee、Mark Cornebise、Mary Harris、I-hsiang Shu、Alan Gill、Julio H. Cuervo、William M. Abraham、Steven P. Adams

  DOI：10.1021/jm020054e

  日期：2002.7.1

  The antigen alpha4beta1 (very late antigen-4, VLA-4) plays an important role in the migration of white blood cells to sites of inflammation. It has been implicated in the pathology of a variety of diseases including asthma, multiple sclerosis, and rheumatoid arthritis. We describe a series of potent inhibitors of alpha4beta1 that were discovered using computational screening for replacements of the peptide region of an existing tetrapeptide-based alpha4beta1 inhibitor (1; 4-[N'-(2-methylphenyl)-ureido]phenylacetyl-Leu-Asp-Val) derived from fibronectin. The search query was constructed using a model of 1 that was based upon the X-ray conformation of the related integrin-binding region of vascular cell adhesion molecule-1 (VCAM-1). The 3D search query consisted of the N-terminal cap and the carboxyl side chain of 1 because, upon the basis of existing structure-activity data on this series, these were known to be critical for high-affinity binding to alpha4beta1. The computational screen identified 12 reagents from a virtual library of 8624 molecules as satisfying the model and our synthetic filters. All of the synthesized compounds tested inhibit alpha4beta1 association with VCAM-1, with the most potent compound having an IC50 of 1 nM, comparable to the starting compound. Using CATALYST, a 3D QSAR was generated that rationalizes the variation in activities of these alpha4beta1 antagonists. The most potent compound was evaluated in a sheep model of asthma, and a 30 mg nebulized dose was able to inhibit early and late airway responses in allergic sheep following antigen challenge and prevented the development of nonspecific airway hyperresponsiveness to carbachol. Our results demonstrate that it is possible to rapidly identify nonpeptidic replacements of integrin peptide antagonists, This approach should be useful in identification of nonpeptidic alpha4beta1 inhibitors with improved pharmacokinetic properties relative to their peptidic counterparts.