CSF1R/colony stimulating factor 1 receptor

一种具有式（1）结构的N-（氮杂芳基）环内酰胺-1-甲酰胺衍生物、其制备方法及其用途，每个取代基在说明书和权利要求书中进行了定义。该化合物可广泛应用于制备用于治疗癌症、肿瘤、自身免疫性疾病、代谢性疾病或转移性疾病的药物，特别是用于治疗卵巢癌症、胰腺癌症、前列腺癌症、乳腺癌症、宫颈癌症、胶质母细胞瘤、多发性骨髓瘤、代谢性病变、神经变性疾病、原发肿瘤部位转移或骨转移性癌症的药物，并有望开发成CSF1R抑制剂药物[1]。

腱鞘巨细胞瘤（TGCT）是一种罕见的局部侵袭性软组织肿瘤，起源于关节滑膜、法氏囊和腱鞘，与集落刺激因子1（CSF-1）基因的过表达有关。吡咪考替尼是一种口服、高选择性和强效的小分子CSF-1受体（CSF-1R）抑制剂，对TGCT患者具有强大的疗效和安全性，目前正在开发用于多种疾病。在一项针对不适合手术的TGCT患者的开放标签I期研究中，匹米考替尼显示出优越的疗效和安全性。在这篇文章中，我们阐明了多区域III期MANEUVER试验（NCT05804045）的基本原理和研究设计，该试验旨在评估吡咪考替尼在亚洲、北美和欧洲不适合手术切除的TGCT患者中的疗效和安全性[2]。

Randomization & Blinding [2]
Approximately 90 eligible participants will be randomized in a 2:1 ratio to pimicotinib 50 mg QD or matching placebo (Figure 1). Randomization will be conducted across all sites using a central interactive web response system and will be stratified by China sites and non-China sites. In Part 1, treatment assignment will remain blinded to participants, investigators, study site personnel, safety laboratory personnel, central imaging readers and reviewers, as well as the sponsor. After all participants complete Part 1 and reach the primary efficacy analysis time point, unblinding (for the sponsor only) and analysis will be conducted following data cleaning and database lock.

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Study interventions [2]
Pimicotinib or matching placebo is administered QD with a dose of 50 mg in Part 1, and the drug can be taken with or without food. Participants will continue with the same dosage in Part 2 (and Part 3, if applicable) as they were receiving at the conclusion of Part 1. The study drug may be interrupted or dose reduced at the investigator's discretion at any time, e.g., due to AEs. A reduction to 25 mg QD is permissible as the maximum dose adjustment. If a participant requires a therapeutic dose below 25 mg QD, they must discontinue from the treatment.

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Safety & AEs [2]
An AE is defined as any untoward medical occurrence, regardless of its causal relationship to the investigational drug, that occurs in a participant from the time of signing the informed consent form until 30 days (including Day 30) after the last dose of study drug. A treatment-emergent adverse event (TEAE) is defined as any adverse event that occurs or worsens after the initiation of treatment in this study, up to 30 days after the last dose of the study drug, following guidance from the US FDA. The severity of AEs will be graded by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

[1]. N-(azaaryl)cyclolactam-1-carboxamide derivative, preparation method and application. World Intellectual Property Organization, WO2018214867 A1. 2018-11-29.

[2]. MANEUVER: A Phase III study of pimicotinib to assess efficacy and safety in tenosynovial giant cell tumor patients. Future Oncol . 2024 Sep 17:1-8.

Pimicotinib is an orally bioavailable inhibitor of colony stimulating factor 1 receptor (CSF1R; CSF-1R; CD115; M-CSFR), with potential immunomodulatory and antineoplastic activities. Upon oral administration, pimicotinib targets and binds to CSF1R, thereby blocking CSF1R activation and CSF1R-mediated signaling. This inhibits the activities of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), and prevents immune suppression in the tumor microenvironment (TME). This enhances antitumor T-cell immune responses and inhibits the proliferation of tumor cells. CSF1R, also known as macrophage colony-stimulating factor receptor (M-CSFR) and CD115 (cluster of differentiation 115), is a cell-surface receptor that plays major roles in tumor cell proliferation and metastasis.

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Tenosynovial giant cell tumor (TGCT) is a rare soft tissue tumor which grows in the soft tissues around joints or parts of the body used for movement. It is caused by high levels of a type of protein called CSF-1. Even though surgery is a preferred treatment option, some patients may be unable to have surgery because of where the tumor is, how complicated it is, or the risk of serious problems or illness after the surgery. Therefore, new treatments that are safe, effective and that help people live well are still needed for this disease. Pimicotinib is a medicine which blocks CSF-1, and researches have shown that it is safe and effective for treating TGCT in smaller, early study. To confirm these results, researchers have started a larger study, known as MANEUVER, in some parts of Asia, North America and Europe. This study will confirm if pimicotinib is safe and effective in patients with TGCT who may not be able to have surgery.Clinical Trial Registration: NCT05804045 (ClinicalTrials.gov).[2]

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The MANEUVER study is structured around a robust three-part design, initiating with a blinded assessment of efficacy and safety, followed by an extended open-label phase that allows for longer observation of secondary end points. Notably, the trial incorporates a placebo crossover component, which is anticipated to strengthen the evidence supporting the efficacy and safety of pimicotinib beyond part 1. Besides objective imaging assessment, most key secondary analyses will focus on several clinical outcome assessments. These measures are critical for demonstrating that pimicotinib offers significant clinical benefits. Furthermore, it is imperative to confirm the absence of conventional hepatotoxicity associated with pimicotinib based on the data from Phase I study. The study's outcomes are expected to clarify pimicotinib's role as a therapeutic option for patients requiring interventions to preserve physical function and enhance quality of life. Most importantly, these results will provide a deeper understanding of disease characteristics and potential variations in response across different populations, i.e. the Chinese and western population. This is the first global trial to enroll both Asian and Western patients with TGCT in balanced proportions across multiple regions. Specifically, Asian participants, primarily from China, constitute half of our study population. This robust representation allows for detailed outcome comparisons by stratification factor – China sites versus non-China sites – thereby facilitating a deeper understanding of disease characteristics and potential variations in response across different populations. While previous research has documented similar anatomical distributions between Chinese and Western patient populations with TGCT, notable disparities in the mean duration from disease onset to diagnosis and histories of previous trauma have been observed [Citation15,Citation16]. This will address critical gaps in existing literature and advance our comprehension of the clinical landscape of TGCT in varied demographic settings.[2]

C22H24N6O3

420.464364051819

420.19

C, 62.84; H, 5.75; N, 19.99; O, 11.42

2253123-16-7

2866305-19-1 (HCl); 2253123-16-7

139549388

White to off-white solid powder

2

102

1

6

4

31

674

0

NXFPMDWYDKHFMM-UHFFFAOYSA-N

InChI=1S/C22H24N6O3/c1-14-18(31-16-7-9-23-17(11-16)15-12-24-27(4)13-15)5-6-19(25-14)26-21(30)28-10-8-22(2,3)20(28)29/h5-7,9,11-13H,8,10H2,1-4H3,(H,25,26,30)

3,3-dimethyl-N-[6-methyl-5-[2-(1-methylpyrazol-4-yl)pyridin-4-yl]oxypyridin-2-yl]-2-oxopyrrolidine-1-carboxamide

pimicotinib [INN]; Pimicotinib (USAN/INN); HV1XI8HST2; ABSK021; ABSK-021; CHEMBL5314535;

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。