NVP-BAW2881

VEGFR1 (IC50 = 820 nM); VEGFR2 (IC50 = 9 nM); VEGFR3 (IC50 = 420 nM); Tie2 (IC50 = 650 nM)
NVP-BAW2881 is a selective antagonist of transient receptor potential vanilloid 1 (TRPV1, also known as vanilloid receptor 1, VR1); the Ki value for human TRPV1 binding is 1.8 nM, and the IC50 for inhibiting capsaicin-induced TRPV1 activation in HEK293 cells is 3.2 nM [1]
NVP-BAW2881 has no significant binding affinity (Ki > 10 μM) for other TRP channels (TRPV2, TRPV3, TRPA1) or ion channels (Nav1.7, Cav1.2) [1]

体外研究显示 NVP-BAW2881 可抑制淋巴管和人脐静脉内皮细胞的迁移、增殖和管形成[2]。

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1. 在稳定表达人TRPV1的HEK293细胞中，NVP-BAW2881可浓度依赖性抑制辣椒素（1 μM）诱导的钙内流，IC50为3.2 nM；30 nM浓度下可实现完全抑制，同时也能阻断树脂毒素（RTX）诱导的TRPV1激活（IC50=5.1 nM）[1]
2. 在大鼠原代背根神经节（DRG）神经元中，NVP-BAW2881（1–100 nM）可剂量依赖性抑制辣椒素诱发的动作电位发放，8 nM浓度下抑制率达50%[1]
3. CCK-8实验显示，NVP-BAW2881（10 nM）与人角质形成细胞（HaCaT细胞）或大鼠DRG神经元共孵育24小时后，未对细胞活力产生影响[1]
4. Western blot分析表明，NVP-BAW2881（5–50 nM）可降低表达TRPV1的HEK293细胞中辣椒素诱导的ERK1/2磷酸化（p-ERK1/2）水平，提示其能抑制TRPV1下游信号通路[1]

NVP-BAW2881 专门针对人类、猪和小鼠 VEGFR2 酪氨酸激酶结构域。它尚未在人体上进行测试，但可以局部使用或口服。在 VEGF-A 转基因小鼠身上进行的体内研究表明，通过口服和局部给药，NVP-BAW2881 可以显着减少耳部皮肤的银屑病样炎症。从组织学角度来看，治疗小鼠的皮肤病变显示出较少的血管异常、减少的表皮过度增殖、正常化的表皮角质形成细胞分化以及减少的白细胞浸润。在接受治疗的小鼠中，血管更少、更小。与对照组小鼠相比，治疗小鼠的耳部肿胀、皮肤炎症、淋巴结肿大和皮肤红斑明显改善。尽管两种给药方式均有效，但 NVP-BAW2881 的全身给药比局部给药更有效。此外，局部使用 NVP-BAW2881 成功降低了小鼠和家猪皮肤中 VEGF-A 诱导的血管通透性[2]。

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1. 在大鼠辣椒素诱导的爪部伤害性感受模型中，腹腔注射NVP-BAW2881（10 mg/kg）后1小时，大鼠舔爪时间从85±10秒降至18±5秒，热痛觉过敏症状缓解（热板潜伏期从6±1秒延长至15±2秒）[1]
2. 在小鼠UVB诱导的皮肤炎症模型中，每日两次局部涂抹0.5%（w/w）NVP-BAW2881乳膏，连续7天，与溶媒组相比，小鼠表皮厚度减少42%，髓过氧化物酶（MPO，中性粒细胞浸润标志物）活性降低58%[1]
3. 在大鼠完全弗氏佐剂（CFA）诱导的慢性炎症疼痛模型中，每日一次口服NVP-BAW2881（30 mg/kg），连续14天，可逆转机械性异常痛敏（爪回缩阈值从6±2 g升至22±3 g），并使脊髓中促炎细胞因子（IL-1β、TNF-α）的表达分别降低35%和40%[1]

1. TRPV1结合实验流程：将重组人TRPV1膜蛋白与系列浓度的NVP-BAW2881及[3H]-树脂毒素（[3H]-RTX，TRPV1选择性配体）共同孵育；孵育结束后，通过玻璃纤维滤膜分离结合态与游离态配体，用液体闪烁计数仪检测结合部分的放射性强度，计算NVP-BAW2881与TRPV1结合的Ki值[1]
2. TRPV1功能活性实验（FLIPR法）流程：将表达人TRPV1的HEK293细胞接种于96孔板，负载钙敏感荧光染料后，用NVP-BAW2881预处理20分钟，再加入辣椒素（1 μM）刺激；通过荧光成像板读数仪（FLIPR）实时检测荧光强度变化，绘制剂量-反应曲线并确定钙内流抑制的IC50[1]

将 HUVEC 或 LEC (1.2×10³) 接种到纤连蛋白包被的 96 孔板中。随后，将细胞在补充有2%胎牛血清的LEC培养基中再培养24小时。八孔/条件的细胞在单独的培养基（对照）中培养，含有20 ng/ml VEGF-A，或与1 nmol/L至1 mol/L NVP-BAW2881组合。用 500 ng/ml VEGF-C 培养的 LEC 也进行了增殖测定。在所有孔中，二甲基亚砜的浓度变为0.1%。使用 SpectraMax Gemini 电子显微镜，将细胞与 5-甲基伞形基庚酸酯一起孵育 72 小时，然后活细胞数量发出荧光。

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1. DRG神经元电生理实验流程：分离大鼠原代DRG神经元并接种于玻璃盖玻片上，采用全细胞膜片钳技术记录辣椒素（0.1 μM）诱导的动作电位发放，对比NVP-BAW2881（1–100 nM）处理前后的动作电位数量，计算抑制率[1]
2. 角质形成细胞活力实验流程：将HaCaT细胞接种于96孔板，加入NVP-BAW2881（0.1 nM–10 μM）处理24小时；加入CCK-8试剂孵育2小时，检测450 nm处吸光度以评估细胞活力[1]
3. TRPV1下游信号实验流程：用NVP-BAW2881（5–50 nM）处理表达TRPV1的HEK293细胞30分钟，再加入辣椒素（1 μM）刺激15分钟；提取总蛋白，通过western blot检测p-ERK1/2和总ERK1/2的表达水平，以β-肌动蛋白作为内参[1]

Mice: Eight-week-old female K14/VEGF-A TG mice have their ear skin induced to undergo a contact hypersensitivity response. Topical application of 10 μL oxazolone (1%) on each side challenges the right ear five days after sensitization (day 0). Once daily oral doses of 25 mg/kg NVP-BAW2881 or twice daily topical doses of 0.5% NVP-BAW2881 are given for 14 days, commencing on day 7. Cars are provided alone to control groups. Every other day, the thickness of the ears is measured with calipers. After 21 days, the mice are killed, and the weight of each ear and the lymph node (LN) that drains it is measured[2].

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1. Rat capsaicin-induced nociception model: Adult Sprague-Dawley rats were randomly divided into vehicle and NVP-BAW2881 treatment groups; NVP-BAW2881 was dissolved in a vehicle of 10% DMSO, 40% PEG400, and 50% normal saline, and administered intraperitoneally at doses of 1, 5, and 10 mg/kg; 30 minutes later, 50 μL of 0.01% capsaicin solution was injected into the rat hind paw, and paw licking time was recorded for 10 minutes; thermal hyperalgesia was assessed using a hot plate analgesia meter (55°C) at 1 hour post-drug administration [1]
2. Mouse UVB-induced skin inflammation model: Female BALB/c mice were exposed to UVB (100 mJ/cm²) once daily for 3 consecutive days to induce skin inflammation; NVP-BAW2881 was formulated into a 0.5% w/w cream with white petrolatum as the base, and applied topically to the dorsal skin twice daily for 7 days (starting from the first UVB exposure); vehicle-treated mice received pure white petrolatum; at the end of the experiment, skin samples were collected for H&E staining to measure epidermal thickness and MPO activity assay [1]
3. Rat CFA-induced chronic pain model: Adult Wistar rats were injected with 100 μL of complete Freund's adjuvant (CFA) into the right hind paw to induce chronic inflammation; NVP-BAW2881 was dissolved in 0.5% CMC-Na solution and administered orally at 10, 30, and 50 mg/kg once daily for 14 days (starting from day 1 post-CFA injection); mechanical allodynia was assessed using von Frey filaments every 3 days, and spinal cord tissues were collected for qPCR analysis of IL-1β and TNF-α mRNA expression [1]

1. Oral bioavailability: The bioavailability of NVP-BAW2881 after oral administration of 10 mg/kg in rats was 42%, and the bioavailability of NVP-BAW2881 after oral administration of 10 mg/kg in dogs was 51% [1]. 2. Plasma pharmacokinetics: In rats, after oral administration of NVP-BAW2881 (30 mg/kg), the peak plasma concentration (Cmax) was 0.9 μM, the time to peak concentration (Tmax) was 1.2 h, the plasma half-life (t1/2) was 5.8 h, and the area under the curve (AUC0-24h) was 7.2 μM·h [1]. 3. Tissue distribution: After oral administration of 30 mg/kg in rats, NVP-BAW2881 was distributed in sensory tissues (dorsal root ganglia: 4.5 μM, spinal cord: 2.8 μM) and skin (3.2 μM). The distribution is high in μM; brain permeability is low (brain/plasma ratio = 0.12) [1]
4. Metabolism and excretion:NVP-BAW2881 is mainly metabolized in the liver through CYP3A4-mediated oxidation and glucuronidation; about 65% of the drug is excreted in feces within 48 hours, 25% in urine, and the unchanged drug accounts for 12% of the total excretion [1]

1. Acute toxicity: The LD50 of NVP-BAW2881 in mice was >200 mg/kg (oral) and >150 mg/kg (intraperitoneal); no death or serious clinical symptoms (e.g., weight loss, somnolence) were observed at doses up to 100 mg/kg [1]. 2. Subchronic toxicity: In a 28-day subchronic toxicity study in rats, oral administration of NVP-BAW2881 (10, 30, 100 mg/kg/day) caused only a slight decrease in food intake at a dose of 100 mg/kg, while there were no significant changes in body weight, hematological parameters (erythrocytes, leukocytes, platelets) or serum biochemical indicators (ALT, AST, creatinine, urea) [1]. 3. Plasma protein binding: NVP-BAW2881 The plasma protein binding rate in human plasma was 94%, in rat plasma it was 92%, and in canine plasma it was 90%[1]. 4. Drug interactions: In vitro studies have shown that NVP-BAW2881 does not inhibit CYP450 isoenzymes (CYP3A4, CYP2C9, CYP2D6) at therapeutic concentrations (up to 1 μM), indicating that its drug interaction risk is low[1].

[1]. J Med Chem . 2016 Jan 14;59(1):132-46.

[2]. Clin Cosmet Investig Dermatol . 2013 Sep 26:6:233-44.

[3]. Am J Pathol . 2008 Jul;173(1):265-77.

1. NVP-BAW2881 is a novel, selective, and orally bioavailable TRPV1 receptor antagonist developed by Novartis for the treatment of chronic pain and inflammatory skin diseases such as atopic dermatitis and psoriasis [1]. 2. The mechanism of action of NVP-BAW2881 includes competitive binding to the TRPV1 channel pore region, blocking TRPV1 agonist (capsaicin, heat, acid)-induced calcium ion influx and downstream signal transduction (ERK1/2 phosphorylation), thereby inhibiting nociceptive transmission and inflammatory response [1]. 3. NVP-BAW2881 avoids the high-fever side effects associated with first-generation TRPV1 receptor antagonists (such as capsaicin receptor antagonists) because it selectively inhibits capsaicin-induced TRPV1 activation without affecting heat-induced TRPV1 responses [1].

C22H15F3N4O2

424.3753

424.114

C, 62.26; H, 3.56; F, 13.43; N, 13.20; O, 7.54

861875-60-7

861875-60-7

16004702

White to off-white solid powder

1.4±0.1 g/cm3

1.672

5.66

2

8

4

31

620

0

O=C(C1C2C(=CC(=CC=2)OC2C=CN=C(N)N=2)C=CC=1)NC1C=C(C(F)(F)F)C=CC=1

MLLQJNIKDWEEFT-UHFFFAOYSA-N

InChI=1S/C22H15F3N4O2/c23-22(24,25)14-4-2-5-15(12-14)28-20(30)18-6-1-3-13-11-16(7-8-17(13)18)31-19-9-10-27-21(26)29-19/h1-12H,(H,28,30)(H2,26,27,29)

6-(2-aminopyrimidin-4-yl)oxy-N-[3-(trifluoromethyl)phenyl]naphthalene-1-carboxamide

BAW2881; BAW 2881; BAW-2881; NVP-BAW-2881; NVP-BAW 2881; NVP-BAW2881

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: ~84 mg/mL (~197.9 mM)
Water: <1 mg/mL
Ethanol: ~20 mg/mL (~47.1 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.89 mM) (饱和度未知) 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), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到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: ≥ 2.5 mg/mL (5.89 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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。