- Integrin αvβ6 (IC50 = 29.8 nM) [3]
- Integrin αvβ1 (IC50 = 19.2 nM) [3]

抑制TGF - β激活：Bexotegrast (PLN - 74809)在体外可抑制整合素αvβ6和αvβ1诱导的TGF - β激活。通过配体结合、细胞黏附以及TGF - β细胞激活实验发现，该药物可通过阻断整合素介导的TGF - β激活途径，减少I型胶原基因的表达，这在特发性肺纤维化患者的肺切片培养实验中得到验证[3]

抗纤维化作用：在博来霉素处理的小鼠中，Bexotegrast (PLN - 74809)可剂量依赖性地抑制肺部Smad3磷酸化和胶原蛋白沉积，减轻肺纤维化负担。其抗纤维化效果优于尼达尼布或吡非尼酮，能更有效地降低纤维化小鼠肺组织中的胶原基因表达[3]

Bleomycin - induced lung fibrosis mouse model: Induce lung fibrosis in mice with bleomycin. Divide the mice into different groups, and administer Bexotegrast (PLN - 74809) to the experimental groups at different doses, while the control group is given a placebo. After a certain period of treatment, sacrifice the mice, collect lung tissues, and detect the changes of pulmonary collagen deposition and Smad3 phosphorylation to evaluate the anti - fibrotic effect of the drug [3]

Pharmacokinetics [2]
Predicted total and unbound exposures (maximum concentration and area under the concentration time curve from Time 0 to 24 hours postdose) of bexotegrast in participants with IPF increased approximately proportionally with dose (see Tables E3 and E4).

Safety and Tolerability through Week 12 [2]
Overall, bexotegrast demonstrated a favorable safety and tolerability profile over 12 weeks of treatment (Tables 2, 3, E1, and E2 in the online supplement). The majority of TEAEs were mild or moderate in severity. The most common TEAEs are presented in Table 2. Diarrhea was the most common TEAE, occurring in 15 participants (16.9%) in the bexotegrast (pooled) group and 3 participants (9.7%) in the placebo group. Of the participants reporting diarrhea, 13/15 (86.7%) participants in the bexotegrast group and 1/3 (33.3%) participants in the placebo group were receiving nintedanib background therapy; one participant (6.7%) with diarrhea in the bexotegrast group was receiving pirfenidone (Table 3). The remaining participant with diarrhea who received bexotegrast monotherapy had preexisting ulcerative colitis. Most events of diarrhea (14/15; 93.3%) were mild to moderate in severity; one participant receiving bexotegrast and pirfenidone had Grade 3 diarrhea. Four participants interrupted bexotegrast treatment because of intercurrent coronavirus disease (COVID-19) (n = 1), diarrhea (n = 2), and ileus and acute kidney injury (n = 1). Two participants discontinued bexotegrast because of mild diarrhea (n = 1 receiving background nintedanib; n = 1 receiving no background therapy and having preexisting ulcerative colitis). Dose reduction of bexotegrast was not allowed per protocol. No serious adverse events were assessed as being related to the study drug.
TEAEs of IPF/pulmonary fibrosis were reported in 2.3% of participants in the bexotegrast group and 9.7% of participants in the placebo group. Only one of these events was reported as an acute exacerbation of IPF in a participant who had completed 12 weeks of treatment with 160 mg bexotegrast and experienced the event 11 days after the last dose. The event was not considered to be drug related and resolved the following day after treatment in hospital with corticosteroids and antibiotics. One participant with gender-age-physiology Stage III IPF and preexisting coronary artery disease and chronic refractory atrial fibrillation in the 320-mg bexotegrast group experienced a serious and fatal adverse event of acute respiratory failure after elective atrioventricular node ablation. There were no notable changes in laboratory parameters, vital signs, physical examination findings, or electrocardiography findings associated with the study drug. Overall, bexotegrast was well tolerated when used in combination with IPF background therapy or when used as monotherapy (Tables 3, E1, and E2).

[1]. De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8. Nat Commun. 2023 Sep 13;14(1):5660.

[2]. Bexotegrast in Patients with Idiopathic Pulmonary Fibrosis: The INTEGRIS-IPF Clinical Trial. Am J Respir Crit Care Med. 2024 Aug 15;210(4):424-434.

[3]. Dual inhibition of αvβ6 and αvβ1 reduces fibrogenesis in lung tissue explants from patients with IPF. Respir Res. 2021 Oct 19;22(1):265.

αv integrins are key regulators of TGF - β activation and fibrogenesis in pulmonary fibrosis models. αvβ6 and αvβ1 are highly expressed in the lung tissue of patients with idiopathic pulmonary fibrosis, but rarely expressed in normal tissues. Bexotegrast (PLN - 74809) is a small - molecule oral drug, which blocks the activation of TGF - β by inhibiting αvβ6 and αvβ1, and may slow down or even stop the fibrosis process in patients with idiopathic pulmonary fibrosis. It is in phase Ⅱ/Ⅲ clinical trials for the treatment of IPF [3]

C27H38CL2N6O3

565.54

2775365-40-5

2376257-44-0

Typically exists as solids at room temperature

PLN-74809 hydrochloride; PLN-74809 HCl; PLN74809 hydrochloride; orb1739963; 2775365-40-5

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。