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

At an IC50 of 6.8 nM, vercirnon (GSK-1605786) sodium inhibits primary CCR9-expressing cells' chemotaxis toward CCL25. Human T cells cultured with retinoic acid (RA) exhibit chemotaxis induced by CCL25, which is inhibited by vercirnonodium. Vercirnonodium has an IC50 of 141 nM and inhibits CCL25-mediated chemotaxis of RA cultured cells in 100% human AB serum. Vercirnonodium, with IC50 values of 6.9 nM and 1.3 nM, respectively, is a strong inhibitor of CCL25-induced chemotaxis in mouse and rat thymocytes [1].

Vercirnon (GSK1605786A) sodium (10, 50 mg/kg; subcutaneous injection; twice daily; starting at 2 weeks of age and up to 12 weeks of age) decreases the severity of intestinal inflammation in the TNFΔARE animal model [1].

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[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 oral anti-inflammatory drug that targets a chemokine receptor protein associated with both Crohn's disease and ulcerative colitis (two major types of inflammatory bowel disease (IBD)). It is currently undergoing clinical trials, NCT01611805 (a Phase I clinical trial in Japan following GSK1605786). Mechanism of Action: Vercirnon is a small-molecule oral drug designed to control the aberrant immune response in IBD by blocking the activity of the CCR9 chemokine receptor. In adults, CCR9 is a highly specific receptor expressed by T cells that selectively migrate to the digestive tract. This migration of T cells to the small and large intestines leads to persistent inflammation, potentially resulting in Crohn's disease or ulcerative colitis—two major types of IBD. Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, affects millions of people worldwide. CCR9 has been identified as a key chemokine receptor mediating local inflammatory responses in the gastrointestinal tract. The CCR9 inhibitor Vercirnon has entered Phase III clinical trials, but there are some shortcomings that we are trying to improve. [3]

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While it has long been recognized that the chemokine receptor CCR9 and its ligand CCL25 are essential for leukocyte entry into the small intestine and for the development of small intestinal inflammation, the role of this chemokine-receptor in colonic inflammation remains unclear. To this end, we compared the colonic CCL25 protein levels in healthy individuals and patients with ulcerative colitis. In addition, we investigated the effects of CCR9 pharmacological inhibition in a mouse model of mdr1a(-/-) ulcerative colitis. Compared with healthy controls, the CCL25 protein level was significantly elevated in colonic samples from patients with ulcerative colitis, a finding consistent with the results in mdr1a(-/-) mice. In mdr1a(-/-) mice, the CCR9 antagonist significantly reduced the degree of colonic atrophy and remodeling and reduced the levels of inflammatory cytokines in the colon. These findings suggest that the CCR9:CCL25 receptor plays a key role in the pathogenesis of ulcerative colitis and suggest that CCR9 antagonists may have therapeutic benefits for patients with colitis. [2] The chemokine system is a diverse class of G protein-coupled receptors responsible for coordinating cell recruitment under homeostatic and inflammatory conditions. Chemokine receptor 9 (CCR9) is a known chemokine receptor that plays a central role in the migration of immune cells to the intestine. CCL25, the only ligand of CCR9, is expressed on the intestinal mucosa and is known to be elevated in intestinal inflammation. To date, there have been no reports of small molecule antagonists against CCR9. We report for the first time a small molecule called CCX282-B, which is a highly bioavailable, selective, and potent oral CCR9 antagonist. CCX282-B inhibits CCR9-mediated Ca²⁺ mobilization and chemotaxis in Molt-4 cells with IC₅₀ values of 5.4 nM and 3.4 nM, respectively. In the presence of 100% human serum, CCX282-B exhibited an IC₅₀ value of 33 nM for inhibiting CCR9-mediated chemotaxis, and the addition of α1-acid glycoprotein did not affect its efficacy. CCX282-B inhibited the chemotaxis of primary cells expressing CCR9 towards CCL25 with an IC50 value of 6.8 nM. CCX282-B showed equivalent inhibitory effects on the CCL25 chemotaxis of both spliceosomes of CCR9 (CCR9A and CCR9B), with IC50 values of 2.8 nM and 2.6 nM, respectively. CCX282-B also inhibited CCR9-mediated chemotaxis in mice and rats. Inhibition of CCR9 with CCX282-B restored the histopathological features of Crohn's disease (such as TNF(ΔARE) mice) to normal. Analyzing the plasma drug concentrations associated with this improvement helps to understand the pharmacokinetic/pharmacodynamic relationship of 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

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

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

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)

Solubility in Formulation 1: 5 mg/mL (10.71 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 5 mg/mL (10.71 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)