TR-14035
(Synonyms: (ALPHAS)-ALPHA-[(2,6-二氯苯甲酰)氨基]-2',6'-二甲氧基联苯-4-丙酸) 目录号 : GC37818
TR-14035 (SB 683698, MDK-1191) is a a dual alpha4beta (α4β) integrin antagonist with IC50 of 7 nM and 87 nM for alpha4beta7 (α4β7) and alpha4beta1 (α4β1), respectively.
Cas No.:232271-19-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
TR-14035 (SB 683698, MDK-1191) is a a dual alpha4beta (α4β) integrin antagonist with IC50 of 7 nM and 87 nM for alpha4beta7 (α4β7) and alpha4beta1 (α4β1), respectively.
[1] Ila Sircar, et al. Bioorg Med Chem. 2002 Jun;10(6):2051-66.
| Cas No. | 232271-19-1 | SDF | |
| 别名 | (ALPHAS)-ALPHA-[(2,6-二氯苯甲酰)氨基]-2',6'-二甲氧基联苯-4-丙酸 | ||
| Canonical SMILES | COC1=C(C2=CC=C(C[C@@H](C(O)=O)NC(C3=C(Cl)C=CC=C3Cl)=O)C=C2)C(OC)=CC=C1 | ||
| 分子式 | C24H21Cl2NO5 | 分子量 | 474.33 |
| 溶解度 | DMSO: ≥ 41 mg/mL (86.44 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1082 mL | 10.5412 mL | 21.0824 mL |
| 5 mM | 0.4216 mL | 2.1082 mL | 4.2165 mL |
| 10 mM | 0.2108 mL | 1.0541 mL | 2.1082 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Pharmacokinetics and metabolism of TR-14035, a novel antagonist of a4ss1/a4ss7 integrin mediated cell adhesion, in rat and dog
Xenobiotica 2005 Apr;35(4):373-89.PMID:16019958DOI:10.1080/00498250500100235.
The pharmacokinetics and disposition of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine (TR-14035), a novel a4ss1/a4ss7 antagonist, were investigated in the rat and dog. Results indicate extensive clearance of TR-14035 and low oral bioavailability, 17% and 13% in the rat and dog, respectively, at an oral dose of 10 mg/kg. At least 63% of the oral dose was absorbed from the gastrointestinal tract in the rat, and about one-third of the intravenous dose was excreted into bile as unchanged drug in the rat and dog. These data indicate that the oral bioavailability of TR-14035 was limited due to significant first-pass metabolism and biliary excretion in the liver. A species-dependent difference in metabolism was observed. The principal metabolite, O-desmethyl TR-14035, observed in rat, dog and probably human, was further conjugated with sulfate in the rat, but never in dog and human, based on in vitro metabolism and in vivo metabolite profile studies. Urinary excretion was a minor elimination route, but an interesting species difference was recognized. TR-14035 was reabsorbed from the rat renal proximal tubules, and by contrast, secreted into the tubules in the dog, probably via active transport systems.
Characterization of hepatobiliary transport systems of a novel alpha4beta1/alpha4beta7 dual antagonist, TR-14035
Pharm Res 2006 Nov;23(11):2646-56.PMID:16969695DOI:10.1007/s11095-006-9102-6.
Purpose: Our previous pharmacokinetic studies have demonstrated that TR-14035, a novel dual antagonist for alpha4beta1/alpha4beta7 integrin, selectively and strongly accumulated in the liver and was mainly excreted in bile as an unchanged drug. In the present study, we investigated the hepatobiliary transport system in detail. Materials and methods: Uptake by hepatocytes and organic anion transporting polypeptide (OATP)-expressing Xenopus laevis oocytes or Flp-In-293 cells was performed in vitro. Biliary excretion was investigated in mdr1a/b-knockout mice, Bcrp-knockout mice and Mrp2-defective Eisai hyperbilirubinemic rats (EHBRs). Results: TR-14035 was taken up by rat and human hepatocytes by an apparently single saturable mechanism with K(m) of 6.7 and 2.1 microM, respectively, and taurocholate and digoxin reduced this uptake. OATP1B1/OATP-C and OATP1B3/OATP8 expressed in oocytes mediated the TR-14035 uptake with K(m) of 7.5 and 5.3 microM, respectively. OATP1B1*15, a genetic variant of OATP1B1, exhibited a decreased transport of TR-14035 compared with OATP1B1*1a. Biliary excretion and total body clearance of unchanged TR-14035 in EHBRs were significantly lower than those in normal rats, while there was no difference in the clearances between wild and mdr1a/b- or Bcrp-knockout mice. Conclusion: These results indicate that OATP1B1 and OATP1B3 are at least partly responsible for the accumulation of TR-14035 into hepatocytes, and Mrp2 principally mediates the biliary excretion of TR-14035. Furthermore, genetic polymorphisms of OATP1B1 may cause an interindividual variability in the pharmacokinetics of TR-14035.
Role of human liver cytochrome P450 2C9 in the metabolism of a novel alpha4beta1/alpha4beta7 dual antagonist, TR-14035
Drug Metab Pharmacokinet 2005 Apr;20(2):127-34.PMID:15855725DOI:10.2133/dmpk.20.127.
The metabolism of a novel dual antagonist for alpha4beta1/alpha4beta7 integrin, TR-14035, and the role of polymorphic enzyme responsible for this metabolism were investigated. Human liver microsomes catalyzed the NADPH-dependent metabolism of TR-14035 to a primary metabolite, O-desmethyl TR-14035. This formation was completely blocked by both sulfaphenazole, a selective CYP2C9 inhibitor, and CYP2C9 antibody, whereas potent inhibitors selective for other CYPs exhibited little effects. Of 12 recombinant CYPs examined, O-desmethyl metabolite was principally formed by CYP2C9. CYP1A1, an extrahepatic enzyme, also had this activity (about one-fourth of CYP2C9). Utilizing recombinant CYP2C9*1, K(m) and V(max)/K(m) values of 23.3 microM and 0.284 microL/min/pmol CYP2C9, respectively, were obtained for the O-desmethyl formation, which were quite similar to those in CYP2C9*2 enzyme. In contrast, V(max)/K(m) value in recombinant CYP2C9*3 was approximately one-sixth of CYP2C9*1 and *2. In agreement, kinetics studies using human liver microsomes with CYP2C9*1/*1, *2/*2 and *3/*3 genotypes revealed that the V(max)/K(m) value in *2/*2 microsomes was comparable to that in wild type microsomes, in contrast, that in *3/*3 microsomes was reduced. These results demonstrate CYP2C9 is a primary enzyme mediating the O-desmethylation of TR-14035 in human liver. In homozygotes of CYP2C9*3, the metabolic clearance of TR-14035 should be decreased compared with homozygotes of CYP2C9*1 or 2.
Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: discovery of TR-14035, a dual alpha(4)beta(7)/alpha(4)beta(1) integrin antagonist
Bioorg Med Chem 2002 Jun;10(6):2051-66.PMID:11937364DOI:10.1016/s0968-0896(02)00021-4.
alpha(4)beta(1) and alpha(4)beta(7) integrins are key regulators of physiologic and pathologic responses in inflammation and autoimmune disease. The effectiveness of anti-integrin antibodies to attenuate a number of inflammatory/immune conditions provides a strong rationale to target integrins for drug development. Important advances have been made in identifying potent and selective candidates, peptides and peptidomimetics, for further development. Herein, we report the discovery of a series of novel N-benzoyl-L-biphenylalanine derivatives that are potent inhibitors of alpha4 integrins. The potency of the initial lead compound (1: IC(50) alpha(4)beta(7)/alpha(4)beta(1)=5/33 microM) was optimized via sequential manipulation of substituents to generate low nM, orally bioavailable dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. The SAR also led to the identification of several subnanomolar antagonists (134, 142, and 143). Compound 81 (TR-14035; IC(50) alpha(4)beta(7)/alpha(4)beta(1)=7/87 nM) has completed Phase I studies in Europe. The synthesis, SAR and biological evaluation of these compounds are described.
α4β7 integrin inhibitors: a patent review
Expert Opin Ther Pat 2018 Dec;28(12):903-917.PMID:30444683DOI:10.1080/13543776.2018.1549227.
The α4β7 integrin is heterodimeric cell surface receptors expressed on most leukocytes. Mucosal addressing cell adhesion molecule 1(MAdCAM-1) is an exclusive ligand for α4β7 integrin. Areas covered: This article will highlight the progress that has been made in the discovery and development of α4β7 integrin inhibitors, and their use in the treatment of inflammatory bowel diseases, multiple sclerosis, asthma, hepatic disorders, human immunodeficiency virus, allergic conjunctivitis and type 1 diabetes. Expert opinion: α4β7 integrin inhibitors have attracted much interest for their clinical implication. Natalizumab and Vedolizumab are monoclonal antibodies (mAbs) successfully utilized clinically. Natalizumab is a mAbs of α4-subunit blocking both α4β1 and α4β7 integrin. Vedolizumab selectively targets the α4β7 integrin. Several mAbs are still in the process of research and development. Among these mAbs, etrolizumab selectively against the β7-subunit and AMG-181 specifically against the α4β7 integrin are the most promising anti-α4β7 integrin antibodies. Despite the unclear development stage of TR-14035 and R411, several low molecular compounds show bright future of further development, such as AJM300 and CDP323. In addition, results from laboratory data show that peptide inhibitors, such as peptide X, are effective α4β7 integrin inhibitors.