CCR9B ( IC50 = 2.6 nM ); CCR9A ( IC50 = 2.8 nM )

vercirnon (GSK-1605786) 钠抑制原代 CCR9 表达细胞对 CCL25 的趋化性，IC50 为 6.8 nM。用视黄酸 (RA) 培养的人 T 细胞表现出由 CCL25 诱导的趋化性，而 CCL25 会被 vercirnonodium 抑制。 Vercirnonodium 的 IC50 为 141 nM，抑制 100% 人 AB 血清中 RA 培养细胞的 CCL25 介导的趋化性。 Vercirnonodium 的 IC50 值分别为 6.9 nM 和 1.3 nM，是 CCL25 诱导的小鼠和大鼠胸腺细胞趋化性的强抑制剂 [1]。

Vercirnon (GSK1605786A) 钠（10、50 mg/kg；皮下注射；每天两次；从 2 周龄开始直至 12 周龄）可降低 TNFΔARE 动物模型中肠道炎症的严重程度 [1]。

CCX282-B抑制了CCR9介导的Molt-4细胞上的钙（2+）动员和趋化性，IC（50）值分别为5.4和3.4 nM。在100%人血清存在的情况下，CCX282-B抑制了CCR9介导的趋化性，IC（50）为33 nM，添加α1-酸性糖蛋白不影响其效力。CCX282-B以6.8nM的IC（50）抑制了原代表达CCR9的细胞对CCL25的趋化性。CCX282-B是两种剪接形式的CCR9（CCR9A和CCR9B）的CCL25导向趋化性的等效抑制剂，IC（50）值分别为2.8和2.6 nM。CCX282-B还抑制了小鼠和大鼠CCR9介导的趋化性[1]。

Animal/Disease Models: C57BL/6 mice (TNFΔARE terminal ileitis mouse model) [1]
Doses: 10, 50 mg/kg
Route of Administration: subcutaneous injection; twice (two times) daily; starting at 2 weeks of age until 12 weeks of age
Experimental Results: Severe inflammation associated with TNF overexpression was completely prevented at a dose of 50 mg/kg. Lower doses were similarly protective.

[1]. Characterization of CCX282-B, an orally bioavailable antagonist of the CCR9 chemokine receptor, for treatment of inflammatory bowel disease. J Pharmacol Exp Ther. 2010 Oct;335(1):61-9.

[2]. CCR9 Antagonists in the Treatment of Ulcerative Colitis. Mediators Inflamm. 2015;2015:628340.

[3]. Biarylsulfonamide CCR9 inhibitors for inflammatory bowel disease. Bioorg Med Chem Lett. 2015 Sep 1;25(17):3661-4.

Vercirnon is a novel, orally active anti-inflammatory agent that targets a chemokine receptor protein implicated in both Crohn's disease and ulcerative colitis, the two principal forms of IBD. It is under investigation in clinical trial NCT01611805 (Japanese Phase I of GSK1605786).

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Mechanism of Action
Vercirnon, a small molecule, orally-available drug, is intended to control the inappropriate immune system response underlying IBD by blocking the activity of the CCR9 chemokine receptor. In adults, CCR9 is a highly specific receptor expressed by T cells that migrate selectively to the digestive tract. The trafficking of T cells to the small and large intestine causes persistent inflammation that may result in Crohn's disease or ulcerative colitis - the two principal forms of IBD.

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Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, affects millions of people worldwide. CCR9 has been shown to be a key chemokine receptor mediating the local inflammatory responses in the GI tract. The CCR9 inhibitor Vercirnon advanced to phase 3 clinical trials, but carries several liabilities which we sought to improve.[3]

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While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a(-/-) mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a(-/-) mice. In the mdr1a(-/-) mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation.[2]

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The chemokine system represents a diverse group of G protein-coupled receptors responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions. Chemokine receptor 9 (CCR9) is a chemokine receptor known to be central for migration of immune cells into the intestine. Its only ligand, CCL25, is expressed at the mucosal surface of the intestine and is known to be elevated in intestinal inflammation. To date, there are no reports of small-molecule antagonists targeting CCR9. We report, for the first time, the discovery of a small molecule, CCX282-B, which is an orally bioavailable, selective, and potent antagonist of human CCR9. CCX282-B inhibited CCR9-mediated Ca(2+) mobilization and chemotaxis on Molt-4 cells with IC(50) values of 5.4 and 3.4 nM, respectively. In the presence of 100% human serum, CCX282-B inhibited CCR9-mediated chemotaxis with an IC(50) of 33 nM, and the addition of α1-acid glycoprotein did not affect its potency. CCX282-B inhibited chemotaxis of primary CCR9-expressing cells to CCL25 with an IC(50) of 6.8 nM. CCX282-B was an equipotent inhibitor of CCL25-directed chemotaxis of both splice forms of CCR9 (CCR9A and CCR9B) with IC(50) values of 2.8 and 2.6 nM, respectively. CCX282-B also inhibited mouse and rat CCR9-mediated chemotaxis. Inhibition of CCR9 with CCX282-B results in normalization of Crohn's disease such as histopathology associated with the TNF(ΔARE) mice. Analysis of the plasma level of drug associated with this improvement provides an understanding of the pharmacokinetic/pharmacodynamic relationship for CCR9 antagonists in the treatment of intestinal inflammation.[1]

C22H21CLN2NAO4S

466.913

466.073

C, 56.59; H, 4.32; Cl, 7.59; N, 6.00; Na, 4.92; O, 13.71; S, 6.87

886214-18-2

Vercirnon;698394-73-9

71300757

Light yellow to yellow solid powder

6.157

103.4

0

5

4

31

862

0

CC(C)(C)C1=CC=C(C=C1)S(=O)(=O)/N=C/2\C=CC(=C\C2=C(/C3=CC=[N+](C=C3)[O-])\[O-])Cl.[Na+]

NKNHYMXTVRJZBC-YBZPVFAISA-M

InChI=1S/C22H21ClN2O4S.Na/c1-22(2,3)16-4-7-18(8-5-16)30(28,29)24-20-9-6-17(23)14-19(20)21(26)15-10-12-25(27)13-11-15;/h4-14,26H,1-3H3;/q;+1/p-1/b21-19-,24-20+;

sodium;(Z)-[(6E)-6-(4-tert-butylphenyl)sulfonylimino-3-chlorocyclohexa-2,4-dien-1-ylidene]-(1-oxidopyridin-1-ium-4-yl)methanolate

Vercirnon sodium; 886214-18-2; Vercirnon sodium [USAN]; UNII-9NQF0M8R0M; 9NQF0M8R0M; GSK1605786A; GSK-1605786A; Benzenesulfonamide, N-(4-chloro-2-((1-oxido-4-pyridinyl)carbonyl)phenyl)-4-(1,1- dimethylethyl)-, sodium salt;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~214.17 mM)

配方 1 中的溶解度: 5 mg/mL (10.71 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 50.0 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 5 mg/mL (10.71 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 50.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。