BT-11
目录号 : GC30803
Omilancor (BT-11) is an orally active lanthionine synthetase C-like 2 (LANCL2) binding compound for treating inflammatory bowel disease (IBD) (Kd value of 7.7 ?M).
Cas No.:1912399-75-7
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
Animal experiment: | Rats: Male Harlan Sprague Dawley rats are treated with a single oral dose of 500 mg/kg and 80 mg/kg/d for 14 days. Treated and control rats are observed for behavioral detriments, and blood and tissues are collected for clinical pathology and histopathological examination[2]. Mice: Wild type and LANCL2−/− male mice are treated with 8 mg/kg/d BT-11 over 8 weeks. Mice are sacrificed and spleens are collected for splenocytes isolation. Cell lysates are collected and cAMP intracellular concentration is measured[1]. |
References: [1]. Carbo A, et al. An N,N-Bis(benzimidazolylpicolinoyl)piperazine (BT-11): A Novel Lanthionine Synthetase C-Like 2-Based Therapeutic for Inflammatory Bowel Disease. J Med Chem. 2016 Nov 23;59(22):10113-10126. | |
Omilancor (BT-11) is an orally active lanthionine synthetase C-like 2 (LANCL2) binding compound for treating inflammatory bowel disease (IBD) (Kd value of 7.7 ?M).
In vitro measurement of cAMP in mouse splenocytes extracted from either WT or LANCL2?/? mice and treated with increasing doses of BT-11 demonstrates BT-11 stimulates cAMP production by activating the LANCL2 pathway[1].
Oral treatment with BT-11 (8 mg/kg/day) ameliorates colitis in mice. Safety assessment in rats indicateds that Oral treatment with BT-11 at high doses has an excellent safety profile up to 1000 mg/kg/day. In a dextran sodium sulfate colitis mouse model, oral administration of BT-11 upregulates the expression of IL-10 and downregulates the expression of TNF-α mRNA. It also upregulates LANCL2 expression in the gastrointestinal tract[1].
[1] Carbo A, et al. J Med Chem. 2016, 59(22):10113-10126.
| Cas No. | 1912399-75-7 | SDF | |
| Canonical SMILES | O=C(N1CCN(C(C2=NC(C3=NC4=CC=CC=C4N3)=CC=C2)=O)CC1)C5=NC(C6=NC7=CC=CC=C7N6)=CC=C5 | ||
| 分子式 | C30H24N8O2 | 分子量 | 528.56 |
| 溶解度 | DMSO : ≥ 30 mg/mL (56.76 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 | 1.8919 mL | 9.4597 mL | 18.9193 mL |
| 5 mM | 0.3784 mL | 1.8919 mL | 3.7839 mL |
| 10 mM | 0.1892 mL | 0.946 mL | 1.8919 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 |
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| % 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。
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Oral Treatment with BT-11 Ameliorates Inflammatory Bowel Disease by Enhancing Regulatory T Cell Responses in the Gut
Inflammatory bowel disease (IBD) is an expanding autoimmune disease afflicting millions that remains difficult to treat due to the accumulation of multiple immunological changes. BT-11 is an investigational new drug for IBD that is orally active, gut restricted, and targets the lanthionine synthetase C-like 2 immunometabolic pathway. CD25+ FOXP3+ CD4+ T cells are increased locally within the colon of BT-11-treated mice in Citrobacter rodentium and IL-10-/- mouse models of colitis. The maintained efficacy of BT-11 in the absence of IL-10 combined with the loss of efficacy when direct cell-cell interactions are prevented suggest that the regulatory T cell (Treg)-related elements of suppression are cell contact-mediated. When PD-1 is inhibited, both in vitro and in vivo, the efficacy of BT-11 is reduced, validating this assertion. The depletion of CD25+ cells in vivo abrogated the retention of therapeutic efficacy postdiscontinuation of treatment, indicating that Tregs are implicated in the maintenance of tolerance mediated by BT-11. Furthermore, the involvement of CD25 suggested a role of BT-11 in IL-2 signaling. Cotreatment with BT-11 and IL-2 greatly enhances the differentiation of CD25+ FOXP3+ cells from naive CD4+ T cells relative to either alone. BT-11 enhances phosphorylation of STAT5, providing a direct linkage to the regulation of FOXP3 transcription. Notably, when STAT5 is inhibited, the effects of BT-11 on the differentiation of Tregs are blocked. BT-11 effectively enhances the IL-2/STAT5 signaling axis to induce the differentiation and stability of CD25+ FOXP3+ cells in the gastrointestinal mucosa to support immunoregulation and immunological tolerance in IBD.
BT-11 improves stress-induced memory impairments through increment of glucose utilization and total neural cell adhesion molecule levels in rat brains
In Oriental medicine, roots of Polygala tenuifolia Willdenow have been known to be an important herb that exhibits sedative effects in insomnia, palpitation with anxiety, restlessness, and disorientation in humans. We previously reported that BT-11, extracted from those roots, improved scopolamine-induced amnesia in rats and inhibited acetylcholinesterase activities in vitro. Therefore, we proposed that BT-11 could remedy stress-induced memory deficits in rats. In this study, the stress-induced memory impairments in rats were significantly reversed almost to the control level by BT-11 treatment. To seek an active component of BT-11 that plays an important role in antipsychotic effects, we compared BT-11 with 3,4,5-trimethoxycinnamic acid (TMCA), which is a constituent of those root extracts. However, the effects of TMCA were less or were not consistent with those of BT-11 in some of tests. In particular, BT-11 reversed the stress-induced reduction of glucose utilization by [(18)fluorodeoxyglucose]FDG-PET and the levels of neural cell adhesion molecule (NCAM) in rat brains to the control levels, whereas TMCA did not. Therefore, BT-11 improved stress-induced memory impairments through increment of glucose utilization and total NCAM levels in rat brains. In conclusion, BT-11 may be strongly effective against stress-induced amnesia in rats, through the combined effects of TMCA and other active components of BT-11.
BT-11 is effective for enhancing cognitive functions in the elderly humans
Roots of Polygala tenuifolia Willdenow have been used in humans for centuries because of its sedative effects. We previously reported that BT-11, extracted from the roots of the plant, improved memory impairments in rats, enhanced memory in normal humans, and inhibited acetylcholinesterase activities in vitro. The present study was a randomized, double-blind, placebo-controlled comparison study to investigate whether BT-11 could enhance memory in the elderly humans. We used the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD) and the Mini-Mental State Examination (MMSE). In the elderly, the total CERAD scores were much more significantly increased in the BT-11-treated group (n=28) than in the placebo-treated group (n=25). Especially, the mean scores of word list recognition, constructional recall and praxis, and modified Boston naming test were markedly improved in BT-11-treated group than in placebo-treated group. In conclusion, BT-11 could enhance some cognitive functions including memory in the elderly humans and therefore may be used as nutraceuticals that provide health benefits, including disease prevention and/or treatment.
Effects of BT-11 on memory in healthy humans
We previously reported that BT-11, the extract of dried roots of Polygala tenuifolia Willdenow, had neuroprotective effects and improved scopolamine- and stress-induced amnesia in rats. It also blocked the activity of acetylcholinesterase and enhanced glucose utilization in the rat brain. Therefore, we examined whether BT-11 could enhance memory in healthy humans. This study was a randomized, double-blind, placebo-controlled, parallel-group study of BT-11 in healthy adults. The participants were given capsules of BT-11 or placebo 3 times daily for 4 weeks. The Korean version of the California Verbal Learning Test (K-CVLT) and the Self-Ordered Pointing Test (SOPT) were used to assess verbal memory and working memory, respectively. The subjects in BT-11-treated group showed more significant increases in immediate recall on the K-CVLT than those in the placebo-treated group. In a comparison within each group, the subjects' scores on most subtests of the K-CVLT were significantly increased by both placebo and BT-11 treatment. Interestingly, the subjects' scores on the recognition subtest of the K-CVLT were significantly increased by BT-11 treatment but not by placebo treatment. Also, BT-11 treatment significantly reduced the number of errors on the SOPT, whereas placebo treatment did not. We are the first to show that BT-11 has memory-enhancing effects and may be a memory-enhancing drug in healthy adults.
Activation of LANCL2 by BT-11 Ameliorates IBD by Supporting Regulatory T Cell Stability Through Immunometabolic Mechanisms
Background: Inflammatory bowel disease (IBD) afflicts 5 million people and is increasing in prevalence. There is an unmet clinical need for safer and effective treatments for IBD. The BT-11 is a small molecule oral therapeutic that ameliorates IBD by targeting lanthionine synthetase C-like 2 (LANCL2) and has a benign safety profile in rats.
Methods: Mdr1a-/-, dextran sodium sulphate , and adoptive transfer mouse models of colitis were employed to validate therapeutic efficacy and characterize the mechanisms of therapeutic efficacy of BT-11. In vitro cultures of CD4+ T cell differentiation and human peripheral blood mononuclear cells from Crohn's disease patients were used to determine its potential for human translation.
Results: BT-11 reduces inflammation in multiple mouse models of IBD. Oral treatment with BT-11 increases the numbers of lamina propria regulatory T cells (Tregs) in a LANCL2-dependent manner. In vitro, BT-11 increases the differentiation in Treg phenotypes, the upregulation of genes implicated in Treg cell stability, and conditions Treg cells to elicit greater suppressive actions. These immunoregulatory effects are intertwined with the ability of BT-11 to regulate late stage glycolysis and tricarboxylic acid cycle. Immunometabolic mechanistic findings translate into human peripheral blood mononuclear cells from healthy individuals and Crohn's disease patients.
Conclusions: BT-11 is a safe, efficacious oral therapeutic for IBD with a human translatable mechanism of action that involves activation of LANCL2, immunometabolic modulation of CD4+ T cell subsets leading to stable regulatory phenotypes in the colonic LP.