methyl 2-(4-hydroxy-3,5-dichlorophenylamino)benzoate | 851961-77-8

• 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: methyl 2-(4-hydroxy-3,5-dichlorophenylamino)benzoate
• 英文别名: methyl 2-(3,5-dichloro-4-hydroxy-anilino)benzoate；Methyl 2-(3,5-dichloro-4-hydroxyphenylamino)benzoate；methyl 2-(3,5-dichloro-4-hydroxyanilino)benzoate
• CAS: 851961-77-8
• 化学式: C₁₄H₁₁Cl₂NO₃
• 分子量: 312.152
• InChiKey: VGXXESBSEOXXGR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  58.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 2-(4-hydroxy-3,5-dichlorophenylamino)benzoate 在 偶氮二甲酸二异丙酯 、 potassium carbonate 、 三苯基膦 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 42.0h， 生成 methyl 2-(3,5-dichloro-4-(2-methoxyethoxy)phenylamino)benzoate
  参考文献：
  名称：

  Kinetic Stabilization of an Oligomeric Protein by a Single Ligand Binding Event

  摘要：

  Protein native state stabilization imposed by small molecule binding is an attractive strategy to prevent the misfolding and misassembly processes associated with amyloid diseases. Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation before misassembly of a partially denatured monomer ensues. Selective stabilization of the native TTR tetramer over the dissociative transition state by small molecule binding to both thyroxine binding sites raises the kinetic barrier of tetramer dissociation, preventing amyloidogenesis. Assessing the amyloidogenicity of a TTR tetramer having only one amyloidogenesis inhibitor (1) bound is challenging because the two small molecule binding constants are generally not distinct enough to allow for the exclusive formation of (TTRI)-I-. in solution to the exclusion of (TTRI2)-I-. and unliganded TTR. Herein, we report a method to tether one fibril formation inhibitor to TTR by disulfide bond formation. Occupancy of only one of the two thyroxine binding sites is sufficient to inhibit tetramer dissociation in 6.0 M urea and amyloidogenesis under acidic conditions by imposing kinetic stabilization on the entire tetramer. The sufficiency of single occupancy for stabilizing the native state of TTR provides the incentive to search for compounds displaying striking negative binding cooperativity (e.g., K-d1 in nanomolar range and K-d2 in the micromolar to millimolar range), enabling lower doses of inhibitor to be employed in the clinic, mitigating potential side effects.

  DOI：

  10.1021/ja042929f
• 作为产物：
  描述：

  邻溴苯甲酸甲酯 在 palladium on activated charcoal tris-(dibenzylideneacetone)dipalladium(0) 、 氢气 、 caesium carbonate 、 (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl 作用下， 以 甲醇 、 乙酸乙酯 、 甲苯 为溶剂， 反应 30.0h， 生成 methyl 2-(4-hydroxy-3,5-dichlorophenylamino)benzoate
  参考文献：
  名称：

  Kinetic Stabilization of an Oligomeric Protein by a Single Ligand Binding Event

  摘要：

  Protein native state stabilization imposed by small molecule binding is an attractive strategy to prevent the misfolding and misassembly processes associated with amyloid diseases. Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation before misassembly of a partially denatured monomer ensues. Selective stabilization of the native TTR tetramer over the dissociative transition state by small molecule binding to both thyroxine binding sites raises the kinetic barrier of tetramer dissociation, preventing amyloidogenesis. Assessing the amyloidogenicity of a TTR tetramer having only one amyloidogenesis inhibitor (1) bound is challenging because the two small molecule binding constants are generally not distinct enough to allow for the exclusive formation of (TTRI)-I-. in solution to the exclusion of (TTRI2)-I-. and unliganded TTR. Herein, we report a method to tether one fibril formation inhibitor to TTR by disulfide bond formation. Occupancy of only one of the two thyroxine binding sites is sufficient to inhibit tetramer dissociation in 6.0 M urea and amyloidogenesis under acidic conditions by imposing kinetic stabilization on the entire tetramer. The sufficiency of single occupancy for stabilizing the native state of TTR provides the incentive to search for compounds displaying striking negative binding cooperativity (e.g., K-d1 in nanomolar range and K-d2 in the micromolar to millimolar range), enabling lower doses of inhibitor to be employed in the clinic, mitigating potential side effects.

  DOI：

  10.1021/ja042929f

文献信息

• [EN] AGENTS FOR USE IN THE TREATMENT OF AMYLOIDOSIS<br/>[FR] AGENTS DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT DE L'AMYLOÏDOSE
  申请人：UCL BUSINESS PLC

  公开号：WO2022058733A1

  公开（公告）日：2022-03-24

  The present invention relates to compounds for stabilising the native tetrameric form of transthyretin and protecting it from proteolytic cleavage; compounds for use in the prevention and treatment of transthyretin amyloidosis; and agents and medicaments comprising such compounds. The compounds are based on a general structure A-L-B, wherein A is a group of formula (II) or of formula (III): or of formula (IV) or of formula (V) B is a group of formula (III), (IV), or (V), or a group of formula (VI) or a group of formula –R10Z, wherein: Z is selected from -CO2R', -CONR'R'', -SO2R' wherein R' and R'' are independently H or C1-C4 alkyl; and R10 is a C1-C4 alkylene or alkenylene group; and L represents a linker group which is a saturated or unsaturated chain of 5 to 13 carbon atoms.

  本发明涉及用于稳定甲状腺素前体蛋白的四聚体形式并保护其免受蛋白水解切割的化合物；用于预防和治疗甲状腺素前体蛋白淀粉样变性的化合物；以及包含此类化合物的药剂和药物。这些化合物基于一般结构A-L-B，其中A是公式(II)或公式(III)的基团：或公式(IV)或公式(V) B是公式(III)、(IV)或(V)的基团，或公式(VI)的基团或公式-R10Z的基团，其中：Z从-CO2R'、-CONR'R''、-SO2R'中选择，其中R'和R''分别是H或C1-C4烷基；而R10是C1-C4烷基或烯基基团；L代表一个由5到13个碳原子组成的饱和或不饱和链的连接基团。
• COMPOUND AND USE THEREOF IN THE TREATMENT OF AMYLOIDOSIS
  申请人：PEPYS Mark Brian

  公开号：US20100249233A1

  公开（公告）日：2010-09-30

  The present invention relates to compounds of formula (I) for stabilizing the tetrameric form of transthyretin, compounds for use in the treatment or prevention of amyloidosis, and agents and medicaments comprising such compounds. wherein X, Y, R 1 , R 2 , R 3 , R 4 , m, n, p, q, and the linker are as defined herein.

  本发明涉及式（I）的化合物，用于稳定甲状腺素转运蛋白四聚体形式，用于治疗或预防淀粉样变性的化合物，以及包含这些化合物的药剂和药物，其中X，Y，R1，R2，R3，R4，m，n，p，q，和连接物如本文所定义。
• Compound and use thereof in the treatment of amyloidosis
  申请人：Pentraxin Therapeutics Ltd.

  公开号：US08236984B2

  公开（公告）日：2012-08-07

  The present invention relates to compounds of formula (I) for stabilizing the tetrameric form of transthyretin, compounds for use in the treatment or prevention of amyloidosis, and agents and medicaments comprising such compounds. wherein X, Y, R1, R2, R3, R4, m, n, p, q, and the linker are as defined herein.

  本发明涉及式（I）化合物，用于稳定甲状腺素转运蛋白四聚体形式，用于治疗或预防淀粉样变性的化合物，以及包含这些化合物的药剂和制剂的药物。其中X、Y、R1、R2、R3、R4、m、n、p、q和连接基如本文所定义。
• US8236984B2
  申请人：——

  公开号：US8236984B2

  公开（公告）日：2012-08-07
• [EN] COMPOUND AND USE THEREOF IN THE TREATMENT OF AMYLOIDOSIS<br/>[FR] COMPOSÉ ET SON UTILISATION POUR LE TRAITEMENT D'UNE AMYLOSE
  申请人：PENTRAXIN THERAPEUTICS LTD

  公开号：WO2009040405A1

  公开（公告）日：2009-04-02

  Agent for stabilising the tetrameric form of transthyretin, which comprises a compound of the general formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein: each Y is independently a direct bond or -CH2-; each X is independently -NH-, -O-, -S-, -CH2-, -NR-, -CO-, -CONH-, -CONR-, -C=N-O-, - NHCO-, -NRCO-, -O-N=C-, -SO-, -SO2- or a direct bond, wherein each of R1, R2, R3 and R4 is independently F, Cl, Br, I, CF3, O CF3, R', OR', NR'R', SOR' or SO2R', wherein R and R' are each independently C1-C3 alkyl which is straight or branched chain or cyclic optionally substituted by one or more halogen atoms; and each m, n, p and q is independently 0 to 4, wherein m+n+p+q>0; and wherein the linker is a linear or branched chain of 7 to 13 carbon atoms in which one or more of the carbon atoms are optionally replaced by a heteroatom, wherein the said chain is unsubstituted or substituted by one or more groups comprising halogen, O, or N atoms, or OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C1-C3 alkoxy.