WO2023066127A1 - 速激肽受体3抑制剂的用途 - Google Patents

速激肽受体3抑制剂的用途 Download PDF

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WO2023066127A1
WO2023066127A1 PCT/CN2022/125106 CN2022125106W WO2023066127A1 WO 2023066127 A1 WO2023066127 A1 WO 2023066127A1 CN 2022125106 W CN2022125106 W CN 2022125106W WO 2023066127 A1 WO2023066127 A1 WO 2023066127A1
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nk3r
inhibitor
kidney
formula
disease
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宋威
徐文浩
李戈锐
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武汉大学
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a new application of a compound, in particular to a new application of a tachykinin receptor 3 (NK3R) inhibitor.
  • a tachykinin receptor 3 (NK3R) inhibitor a tachykinin receptor 3 (NK3R) inhibitor.
  • Chronic kidney disease has become a worldwide public health problem.
  • the incidence of chronic kidney disease in adults in my country was as high as 11%, and the growth rate of chronic kidney disease will exceed 17% in the next ten years.
  • Chronic kidney disease refers to chronic kidney structure and dysfunction caused by various reasons (history of kidney damage is greater than 3 months), including renal tubular lesions, glomerular filtration rate (Glomerular Filtration Rate, GFR) pathological damage, blood or Abnormal urine composition, abnormal imaging examination, or unexplained decrease in GFR ( ⁇ 60ml/min ⁇ 1.73m2) for more than 3 months.
  • GFR glomerular Filtration Rate
  • Chronic kidney disease is irreversible, and most patients with kidney disease need to rely on and accept long-term drug treatment to control and delay the disease.
  • the market size of China's kidney disease drug market was 28.74 billion yuan, and the global drug market size was 151.98 billion US dollars.
  • the main risk factors leading to chronic kidney disease are hypertension, diabetes, cancer,
  • Cancer-related kidney injury includes chronic kidney disease and acute kidney injury, which may be caused by direct damage to the kidney by chemotherapy drugs, invasion and compression of the urinary system by tumors, and prerenal kidney injury caused by systemic consumption [5] .
  • end-stage renal disease uremia leads to metabolic and immune disorders in the body, which will also cause and aggravate organ failure, and chronic kidney disease will also reduce the survival rate of cancer patients.
  • NK3R tachykinin receptor 3, tachykinin receptor 3
  • NK3R is a G protein-coupled receptor, and this molecule has been extensively studied in the field of growth and reproduction.
  • NK3R is expressed in various tissues of mammals.
  • NK3R expressed in the nervous system has been shown to be associated with a variety of neurological diseases, including mood disorders, Alzheimer's disease, Parkinson's disease, schizophrenia, etc. [6] .
  • NK3R is also highly expressed in tissues such as kidney and bladder, but its effect on the urinary system is unknown.
  • NK3R is an important regulatory factor that mediates tumor damage to kidney function. Inhibiting NK3R can greatly improve kidney function without affecting tumor growth.
  • Fezolinetant is an effective selective inhibitor of NK3R, the molecular formula is C 16 H 15 FN 6 OS, the molecular weight is 358.4 g/mol, and the structural formula is shown in formula (I).
  • the Ki of inhibiting NK3R in vitro is 25nM, and the IC50 is 20nM. Phase II clinical trials have found that it can significantly improve hot flashes in postmenopausal women [8] , and Phase II clinical trials for polycystic ovary syndrome are underway.
  • Pavinetant is another effective selective inhibitor of NK3R, the molecular formula is C 26 H 25 N 3 O 3 S, the molecular weight is 459.6 g/mol, and the structural formula is shown in formula (II).
  • the IC50 of its in vitro inhibition was 7.1 and 19.8 ⁇ M, respectively.
  • Phase 2 clinical trials found that it can significantly improve polycystic ovary syndrome and hot flashes [7] .
  • the purpose of the present invention is to provide a new application of NK3R inhibitors.
  • NK3R inhibitors Pavinetant and Fezolinetant may be effective in the treatment of cancer kidney damage potentially effective drugs.
  • a use of an NK3R inhibitor in the preparation of a medicament for treating chronic kidney disease is provided, and the structure of the NK3R inhibitor is shown in formula (I) or formula (II).
  • the NK3R inhibitor is used for the treatment of chronic kidney disease selected from the group consisting of glomerulonephritis, cryptic nephritis, pyelonephritis, Henoch-Schonlein purpura nephritis, lupus erythematosus nephritis, gouty nephropathy, nephropathy syndrome, membranous nephropathy, nephrotic syndrome, diabetic nephropathy, hypertensive nephropathy, and polycystic kidney disease.
  • chronic kidney disease selected from the group consisting of glomerulonephritis, cryptic nephritis, pyelonephritis, Henoch-Schonlein purpura nephritis, lupus erythematosus nephritis, gouty nephropathy, nephropathy syndrome, membranous n
  • the present invention provides the use of NK3R inhibitors in the preparation of medicines, the medicines are used to treat or alleviate renal tubular damage caused by tumors, and the structure of the NK3R inhibitors is as shown in formula (I) or formula ( II) shown.
  • the NK3R inhibitor of the present invention is used to treat or prevent kidney disease caused by advanced tumors.
  • the present invention finds that two NK3R inhibitors, Fezolinetant and Pavinetant, can be used to alleviate renal tubular damage caused by tumors.
  • Drosophila experiments have shown that overexpressing the activated proto-oncogene yki in Drosophila intestinal stem cells can induce significant hyperglycemia and ascites accumulation, and adding NK3R inhibitors Fezolinetant (100 ⁇ M) and Pavinetant (100 ⁇ M) to food for 6 days can The ascites of Drosophila was significantly relieved, and the blood sugar returned to normal.
  • C57BL/6J-APCMin/+ mice are a well-established intestinal adenoma model. Further experiments found that NK3R was highly expressed in renal tubules.
  • C57BL/6J-APCMin/+ mice began to lose weight at the age of 16 weeks, and compared with normal C57BL/6J mice, the urine output decreased by about 30%, and kidney HE staining showed severe damage to the renal tubules .
  • MFC Mae forestomach carcinoma
  • tumors are colonized in the peritoneal cavity of mice. As the tumor grows, it can cause severe ascites and renal tubular damage in mice.
  • NK3R inhibitor Pavinetant 50mg/kg/day
  • the NK3R inhibitor of the present invention can significantly restore renal tubule damage caused by tumors, and is conserved in various tumor models.
  • the chronic kidney disease in the present invention refers to the phenotypes of chronic kidney disease such as oliguria or accumulation of ascites in late stage of tumor patients.
  • Nephropathy or renal tubular damage caused by tumors of the present invention refers to: ascites accumulation, weight gain (mainly ascites), and expansion of renal tubules in MFC tumor mice; tubule dilation. At the physiological level, ascites accumulation or decreased urine output; at the tissue level, renal tubular damage, including renal tubular dilation, and changes in a series of molecular markers of damage.
  • Figure A shows the phenotype and tumor morphology of Drosophila ascites
  • Figure B shows the blood sugar and triglyceride levels of Drosophila
  • C shows the ascites ratio of Drosophila, Non is blank, F10 is Fezolinetant 10 ⁇ M, F100 is Fezolinetant 100 ⁇ M, P10 Pavinetant 10 ⁇ M, P100 is Pavinetant 100 ⁇ M;
  • the left picture shows the antibody ABclonalA7220, and the right picture shows the antibody abcam ab124025, and the immunohistochemical staining was performed on the kidney of C57BL/6 mice.
  • Figure E shows the weight change of C57BL/6 and C57BL/6J-APCMin/+ mice
  • Figure F shows urine volume
  • Figure G shows HE staining of kidney longitudinal section, and F10 is Fezolinetant 10mg/kg, day;
  • the graph H represents the body weight change of mice with C57BL/6 and MFC tumors;
  • the graph I represents the volume of ascites in the mice;
  • the graph J represents the expression level of the renal tubular injury marker gene NGAL;
  • the graph K represents the HE staining of the longitudinal section of the kidney, and Pavi10 is 10 mg/ kg/day, Pavi50 is 50mg/kg/day.
  • NK3R antibody 1 ABclonal Company, product number A7220;
  • NK3R antibody 2 abcam company, product number ab124025;
  • Fezolinetant MedChemExpress (MCE), product number HY-19632, 200mg;
  • Pavinetant MedChemExpress Company (MCE), article number HY-14432, 1g, customized.
  • Drosophila with Yki activation prepared by the laboratory, obtained by crossing esg-GAL4, tub-GAL80 TS , UAS-GFP and UAS-yki.3SA, the literature has been published, pubmed number 34407411
  • mice C57BL/6J-APCMin/+ mice (Jicui Yaokang, catalog number T001457, genotype B6/JGpt-Apcem1Cin(Min)/Gpt)
  • Control group C57BL/6J mice (Jicui Yaokang, Cat. No. N000013)
  • MFC tumor cells ProCell, Procell, Cat. No. CL-0156, 1X10 6 cells/T25 culture flask
  • yki tumors Activated forms of yki tumors (genotypes esg-Gal4, UAS-GFP, tub-Gal80TS/+; UAS-yki3SA/+) were induced in the Drosophila gut by initiating gene expression at 29 degrees Celsius, respectively, in food supplemented with DMSO, Fezolinetant (10 ⁇ M, 100 ⁇ M), Pavinetant (10 ⁇ M, 100 ⁇ M), compared with the control group (esg-Gal4, UAS-GFP, tub-Gal80TS/+) after feeding for 8 days, observed the phenotype and detected the growth of intestinal tumors And systemic glycolipid changes, statistical ascites ratio. see picture 1.
  • NK3R is highly expressed in mouse renal tubules
  • NK3R was highly expressed in the renal tubules but not glomeruli of mice.
  • the C57BL/6J-APCMin/+ mouse is a well-established mammalian intestinal adenoma model commonly used to study tumor-induced host depletion.
  • C57BL/6J-APCMin/+ mice exhibited severe renal tubular damage at the late stage of tumorigenesis and significantly decreased urine output compared with normal mice.
  • MFC tumor (Mouse forestomach carcinoma) colonizes the peritoneal cavity of mice and is a common tumor that can cause ascites. As the tumor grows, it can cause severe ascites and renal tubular damage in mice.
  • NK3R inhibitor Pavinetant (50mg/kg/day) can significantly inhibit the production of ascites, and can alleviate renal tubular lesions.

Abstract

本发明提供NK3R抑制剂在制备药物中的用途，所述药物用于治疗慢性肾病，所述NK3R抑制剂结构如式(I)或式(II)所示。

Description

速激肽受体3抑制剂的用途 技术领域
本发明涉及化合物的新用途，具体地涉及速激肽受体3(NK3R)抑制剂的新用途。
背景技术
1.1慢性肾病(Chronic kidney disease,CKD)
慢性肾病已成为世界公共卫生问题。2016年我国成人慢性肾病发病率高达11％，在未来十年内，慢性肾脏病增长率将超过17％。慢性肾脏病是指各种原因引起的慢性肾脏结构和功能障碍(肾脏损害病史大于3个月)，包括肾小管病变、肾小球滤过率(Glomerular Filtration Rate，GFR)的病理损伤、血液或尿液成分异常，及影像学检查异常，或不明原因GFR下降(<60ml/min·1.73m2)超过3个月。慢性肾病不可逆转，大部分肾病患者需要依赖和接受长期药物治疗来控制和延缓病情，2016年中国肾病用药市场的市场规模为287.4亿元，全球用药市场规模为1519.8亿美元。导致慢性肾脏病的主要危险因素是高血压、糖尿病、癌症、衰老和药物性损害等。
1.2癌症与肾病
癌症新发病例数的增加和生存时间的延长带来患者数量的增加，全世界近9百万人群肿瘤患者，其中60％为恶性，肿瘤导致并发症包括癌症相关肾病是近四分之一癌症患者的直接死因 [1][4]。癌症相关的肾损伤包括慢性肾脏病和急性肾损伤，可能源于化疗药物对肾脏的直接损伤、肿瘤对于泌尿系统的侵犯及压迫，以及全身消耗引起的肾前性肾损伤 [5]。另一方面，终末期肾病(尿毒症)导致体内代谢和免疫紊乱，也将引起并加重器官衰竭，合并慢性肾脏病也将降低癌症患者的生存率。因此合并肾损伤的癌症患者的综合治疗与管理也需要合理优化，对肾功能的保护和肾损伤的治疗也需要引起重视。然而由于癌症导致肾脏损伤的发病机制未明，其治疗一直以姑息性治疗为主 [2]，即使在美国，食品和药物管理局尚未批准任何药物用于癌症并发症的治疗 [3]。因此治疗癌症相关肾病的药物有待进一步的研制与开发。
2.NK3R抑制剂
2.1 NK3R的功能及表达情况
NK3R(tachykinin receptor 3，速激肽受体3)是一种G蛋白耦连受体，该分子在生长和生殖领域有广泛的研究。NK3R在在哺乳动物的多种组织中均有表达。其中，在神经系统中表达的NK3R被证明与多种神经疾病相关，包括心境障碍、阿尔兹海默病、帕金森病、精神分裂症等 [6]。NK3R在肾、膀胱等组织也高表达，然而其对泌尿系统的影响未知。我们首次发现NK3R是介导肿瘤破坏肾脏功能的重要调控因子，抑制NK3R在不影响肿瘤生长的前提下，极大的改善了肾脏功能。
2.2小分子抑制NK3R的信息
Fezolinetant是有效的NK3R选择性抑制剂，分子式为C 16H 15FN 6OS，分子量为358.4g/mol，结构式如式(I)所示。体外抑制NK3R的Ki为25nM，IC50为20nM。2期临床试验发现其对绝经后女性的潮热有明显改善作用 [8]，针对多囊卵巢综合症的二期临床试验正在进行。
Figure PCTCN2022125106-appb-000001
Pavinetant是另一种有效的NK3R选择性抑制剂，分子式为C 26H 25N 3O 3S，分子量为459.6g/mol，结构式如式(II)所示。通过细胞色素P450-3A4酶活试验中咪达唑仑和睾酮测试发现其体外抑制IC50分别为7.1and 19.8μM。2期临床试验发现对多囊卵巢综合症和潮热有明显改善作用 [7]。
Figure PCTCN2022125106-appb-000002
然而用这两种抑制剂阻滞NK3R对肾功能的影响目前尚未见报道。
发明内容
本发明的目的是提供NK3R抑制剂的新用途。
前期研究发现在荷瘤果蝇和小鼠模型中应用这两种抑制剂，可促进排尿，改善肾功能，减轻肾损伤，缓解腹水产生，结果表明NK3R抑制剂Pavinetant和Fezolinetant可能是治疗癌症肾损伤的潜在有效药物。
根据本发明的一方面，提供NK3R抑制剂在制备药物中的用途，所述药物用于治疗慢性肾病，所述NK3R抑制剂结构如式(I)或式(II)所示。
在本发明的优选实施方案中，将NK3R抑制剂用于治疗慢性肾病，所述慢性肾病选自肾小球肾炎、隐匿性肾炎、肾盂肾炎、过敏性紫癜肾炎、红斑狼疮肾炎、痛风肾病、肾病综合征、膜性肾病、肾病综合征、糖尿病肾病、高血压肾病和多囊肾。
根据本发明的另一方面，本发明提供NK3R抑制剂在制备药物中的用途，所述药物用于治疗或缓解肿瘤导致的肾小管损伤，所述NK3R抑制剂结构如式(I)或式(II)所示。
更优选的是，将本发明的NK3R抑制剂用于治疗或预防晚期肿瘤导致的肾病。
本发明发现两种NK3R抑制剂Fezolinetant，Pavinetant可应用于在缓解肿瘤导致的肾小管损伤。
果蝇实验证明，在果蝇肠道干细胞中过表达活化的原癌基因yki，能诱导显著的高血糖和腹水堆积，食物中添加NK3R抑制剂Fezolinetant(100μM)和Pavinetant(100μM)喂养6天能显著缓解果蝇的腹水，血糖也恢复正常。C57BL/6J-APCMin/+小鼠是一个成熟的肠道腺瘤模型。进一步实验发现NK3R在肾小管中有很高的表达。更重要的是，C57BL/6J-APCMin/+小鼠16周龄开始表现体重下降，且相对于正常C57BL/6J小鼠而言，排尿量下降约30％，肾脏HE染色发现肾小管出现严重损伤。腹腔注射NK3R抑制剂Fezolinetant(10mg/kg/day)9天显著恢复C57BL/6J-APCMin/+小鼠排尿量，肾小管的损伤包括肾小管的扩张也得到恢复。MFC(Mouse forestomach carcinoma)肿瘤定植于小鼠腹腔，随着肿瘤的生长，能引起小鼠严重腹水和肾小管损伤。实验发现，腹腔注射1.5x10 7个MFC肿瘤细胞，在第6天即可导致严重的腹水，在注射肿瘤 细胞24小时后，连续腹腔注射NK3R抑制剂Pavinetant(50mg/kg/day)5天能显著抑制腹水的产生，且能缓解肾小管病变，主要包括肾小管的扩张。因此，本发明的NK3R抑制剂能显著恢复肿瘤导致的肾小管损伤，且在多种肿瘤模型中都是保守的。
术语描述：
本发明所述的慢性肾病是指：肿瘤患者晚期表现出尿少、或者腹水堆积等慢性肾病的表型。
本发明所述的肿瘤导致的肾病或肾小管损伤是指：MFC肿瘤小鼠中的腹水堆积、体重增加(主要是腹水)、肾小管的扩张；Apc Min/+小鼠中尿量减少、肾小管扩张。患者生理层面，腹水堆积或尿量减少；组织层面，肾小管损伤，包括肾小管扩张、一系列损伤的分子标记物的变化。
附图简要说明
图1.NK3R抑制剂对于肠道肿瘤引起的果蝇腹水的影响；
其中A图表示果蝇腹水表型和肿瘤形态；B图表示果蝇的血糖和甘油三酯水平；C图表达果蝇的腹水比率，Non为空白，F10为Fezolinetant 10μM,F100为Fezolinetant 100μM,P10为Pavinetant 10μM,P100为Pavinetant 100μM；
图2.免疫组化表明NK3R在小鼠肾小管中表达；
其中左图为抗体ABclonalA7220，右图为抗体abcam ab124025，对C57BL/6小鼠肾脏进行免疫组化染色。
图3.NK3R抑制剂对肠道腺瘤引起的肾脏损伤的影响；
其中E图表示C57BL/6和C57BL/6J-APCMin/+小鼠的体重变化；F图表示尿量；G图表示肾脏纵切HE染色，F10为Fezolinetant 10mg/kg、day；
图4.NK3R抑制剂对前胃癌细胞瘤引起的腹水和肾脏损伤的影响；
其中H图表示C57BL/6和MFC肿瘤小鼠的体重变化；I图表示小鼠腹水体积；J图表示肾小管损伤标志基因NGAL的表达水平；K图表示肾脏纵切HE染色，Pavi10为10mg/kg/day，Pavi50为50mg/kg/day。
具体实施方式
以下通过对较佳实施方式的描述，详细说明但不限制本发明。
材料来源：
NK3R抗体1:ABclonal公司，货号A7220；
NK3R抗体2:abcam公司，货号ab124025；
Fezolinetant：MedChemExpress公司(MCE)，货号HY-19632，200mg；
Pavinetant：MedChemExpress公司(MCE)，货号HY-14432，1g，订制。
实验动物：Yki活化的果蝇(实验室自备，由esg-GAL4,tub-GAL80 TS,UAS-GFP和UAS-yki.3SA杂交获得，文献已发表，pubmed编号34407411)
C57BL/6J-APCMin/+小鼠(集萃药康，货号T001457，基因型B6/JGpt-Apcem1Cin(Min)/Gpt)
对照组C57BL/6J小鼠(集萃药康，货号N000013)
MFC肿瘤细胞(ProCell，普诺赛公司，货号CL-0156，1X10 6细胞/T25培养瓶)
其他材料均为商业购买。
【实施例1】NK3R抑制剂对于肠道肿瘤引起的果蝇腹水的影响
在果蝇肠道干细胞中过表达活化的原癌基因yki能导致肠道干细胞恶性增殖，进而生成肿瘤，肿瘤的生成严重损害了果蝇马氏管的分泌功能，导致果蝇血淋巴的循环水不能被排出体外，出现严重的腹水表型。
方法：通过29摄氏度启动基因表达，在果蝇肠道中诱导活化形式的yki肿瘤(基因型为esg-Gal4,UAS-GFP,tub-Gal80TS/+；UAS-yki3SA/+)，在食物中分别添加DMSO，Fezolinetant(10μM,100μM)，Pavinetant(10μM,100μM)，喂食8天后与对照组(esg-Gal4,UAS-GFP,tub-Gal80TS/+)相比，观测表型、检测肠道肿瘤生长情况和全身糖脂变化、统计腹水比率。见图1。
结果：100μM的NK3R抑制剂均能显著抑制果蝇腹水，恢复血糖水平。
【实施例2】NK3R在小鼠肾小管中高表达
方法：C57BL/6J雄性小鼠，7-8周龄，取肾脏切片，用2种不同NK3R抗体分别做免疫组化(一抗稀释倍数：ABclonalA7220，1:200；abcamAb124025，1:200)，染色观察NK3R在肾脏中的表达。见图2。
结果：NK3R在小鼠的肾小管而不是肾小球中高表达。
【实施例3】NK3R抑制剂对肠道腺瘤引起的肾脏损伤的影响；
C57BL/6J-APCMin/+小鼠是成熟的哺乳动物肠道腺瘤模型，常用于研究肿瘤 导致的宿主消耗。C57BL/6J-APCMin/+小鼠在肿瘤发生晚期会出现严重的肾小管损伤，同时相比于正常小鼠，尿量显著减少。
方法：对照组C57BL/6J和实验组C57BL/6J-APCMin/+雄性小鼠(每组各7只)在正常饲养条件下生长至16周龄，实验组开始出现体重下降即开始给药，分别通过腹腔注射Fezolinetant(0,10mg/kg/day)，连续注射9天，检测体重、尿量，取肾脏染色观察肾小管形态。见图2。
结果：腹腔注射NK3R抑制剂Fezolinetant(10mg/kg/day)显著恢复C57BL/6J-APCMin/+小鼠排尿量，肾小管的损伤也得到恢复。
【实施例4】NK3R抑制剂对前胃癌细胞瘤引起的腹水和肾脏损伤的影响；
MFC肿瘤(Mouse forestomach carcinoma)定植于小鼠腹腔，是常见的能引起腹水的肿瘤。随着肿瘤的生长，能引起小鼠严重腹水和肾小管损伤。
方法：C57BL/6J雄性小鼠，4-6周龄，实验组C57BL/6J小鼠(每组各6只)腹腔注射1.5x10 7个MFC肿瘤细胞，24小时后分别腹腔注射抑制剂Pavinetant(0，10，50mg/kg/day)，连续给药5天后与对照组C57BL/6(每组6只)比较，检测体重、腹水、尿量，取肾脏染色观察肾小管形态。见图3。
结果：NK3R抑制剂Pavinetant(50mg/kg/day)能显著抑制腹水的产生，且能缓解肾小管病变。
参考文献
[1]ZHU X,CALLAHAN M F,GRUBER K A,et al.Melanocortin-4 receptor antagonist TCMCB07 ameliorates cancer-and chronic kidney disease-associated cachexia[J].J Clin Invest,2020,130(9):4921-4934.
[2]崔久嵬,李薇,许红霞,等.肿瘤恶液质临床诊断与治疗指南(2020版)[J].中国肿瘤临床,2021,48(08):379-385.
[3]ROELAND E J,BOHLKE K,BARACOS V E,et al.Management of Cancer Cachexia:ASCO Guideline[J].J Clin Oncol,2020,38(21):2438-2453.
[4]LAUNAY-VACHER V,JANUS N,DERAY G.Renal insufficiency and cancer treatments[J].ESMO open,2016,1(4):e91.
[5]MALYSZKO J,TESAROVA P,CAPASSO G,et al.The link between kidney disease and cancer:complications and treatment[J].Lancet,2020,396(10246): 277-287.
[6]ZHANG W,WANG Y,CHU Y.Tacr3/NK3R:Beyond Their Roles in Reproduction[J].ACS Chemical Neuroscience,2020,11(19):2935-2943.
[7]GEORGE J T,KAKKAR R,MARSHALL J,et al.Neurokinin B Receptor Antagonism in Women With Polycystic Ovary Syndrome:A Randomized,Placebo-Controlled Trial[J].The Journal of Clinical Endocrinology & Metabolism,2016,101(11):4313-4321.
[8]FRASER G L,LEDERMAN S,WALDBAUM A,et al.A phase 2b,randomized,placebo-controlled,double-blind,dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause[J].Menopause,2020,27(4):382-392.

Claims (4)

  1. 速激肽受体3抑制剂在制备治疗慢性肾病药物中的用途，其中所述速激肽受体3抑制剂的结构如式(I)或式(II)所示：
    Figure PCTCN2022125106-appb-100001
  2. 根据权利要求1所述的用途，其中所述慢性肾病选自肾小球肾炎、隐匿性肾炎、肾盂肾炎、过敏性紫癜肾炎、红斑狼疮肾炎、痛风肾、iga肾病、肾病综合征、膜性肾病、肾病综合征、糖尿病肾病、高血压肾病和多囊肾。
  3. 速激肽受体3抑制剂在制备治疗疾病药物中的用途，其中所述疾病为由肿瘤导致的肾小管损伤或肾病，所述速激肽受体3抑制剂的结构如式(I)或式(II)所示：
    Figure PCTCN2022125106-appb-100002
  4. 根据权利要求3所述的用途，其中所述疾病为肿瘤晚期的肾损伤。
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