CN116459260A - 一种特异性靶向nlrp3炎症小体抑制剂的用途 - Google Patents
一种特异性靶向nlrp3炎症小体抑制剂的用途 Download PDFInfo
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Abstract
本发明公开了一种特异性靶向NLRP3炎症小体抑制剂的用途。5‑FUMCL明显抑制LPS诱导的急性全身性炎症模型中IL‑1β和IL‑6的分泌，对于经腹腔、膝关节腔注射MSU诱导的急性腹膜炎、痛风性关节炎的炎性细胞因子IL‑1β、IL‑6和IL‑18具有显著的抑制作用，能显著减少腹腔中中性粒细胞数量、改善膝关节的肿胀程度，而在敲除了NLRP3分子的模型中未显示出相应的抗炎功效。本发明的实验结果提示5‑FUMCL为特异性靶向NLRP3炎症小体抑制剂，并且可作为活性成分制备用于预防或治疗NLRP3炎症小体相关疾病的药物，尤其对急性全身性炎症、急性腹膜炎、痛风性关节炎等炎症相关疾病具有显著的治疗效果。
Description
技术领域
本发明属于医药技术领域，涉及特异性靶向NLRP3炎症小体抑制剂，具体涉及5-FUMCL的抗炎用途。
背景技术
炎症是生物机体在受到外界侵害或者环境压力下产生的自我保护反应，对维持机体健康起着非常重要的作用。但机体产生长期不可控的炎症会引发机体损伤，进而导致疾病的发生。自2002年Tschopp实验室首次提出炎症小体的概念后，针对NLRP3炎症小体的研究成为热点领域。NLRP3包括三个结构域：N端的热蛋白结构域(PYD)、ATP催化功能的核苷酸结合寡聚化区域(NACHT)和C端的富含亮氨酸重复序列(LRR)。宿主通过识别病原体相关的分子模式(PAMPs)和损伤相关分子模式(DAMPs)诱导核因子κB(nuclear factor-κB,NF-κB)活化，进而引发NLRP3的激活，激活的NLRP3的热蛋白样结构域(PYD)与ASC的PYD结构域绑定结合，并与ASC螺旋组装形成ASC斑点。随后，ASC的Caspase募集结构域(CARD)和pro-caspase-1的CARD进行交互结合，并以Procaspase-1的寡聚体形式通过自身的蛋白水解切割产生caspase-1，进而通过介导白介素IL-1β和IL-18的加工、成熟和分泌，以及调控炎症相关基因表达等方式产生各种生物学效应，从而引起炎症。而caspase-1还会将消皮素D(gasdermin D，GSDMD)切割成N端消皮素(N terminal gasdermin-D)，从而产生膜孔，并引起细胞焦亡(pyroptosis)。
NLRP3炎症小体的过度激活与多种疾病相关，包括Cryopyrin相关周期性综合征(CAPS)、家族性寒冷型自身炎症综合征(FCAS)、Muckle-Wells二氏综合征(MWS)、炎症性肠病(IBD)、Ⅱ型糖尿病、肥胖、非酒精性脂肪肝炎、衰老、动脉粥样硬化、痛风、肾脏功能紊乱、阿尔茨海默症(AD)、帕金森综合征、脓毒血症、内毒素血症、腹膜炎、战创伤、心血管应激、心肌肥大，并与多种癌症相关，如结肠癌、乳腺癌、黑色素瘤、丙型肝炎病毒相关的肝细胞癌和胃肠癌等。
NLRP3炎症小体处于炎性细胞因子的上游，是炎症相关疾病的重要启动因素，已成为开发新型和特异性抗炎药物的重要靶标。然而现有NLRP3炎症小体相关疾病的临床治疗药物主要是通过间接抑制NLRP3炎症小体组成成分或相关信号事件而起作用，如IL-18受体拮抗剂、IL-1β中和抗体以及IL-18受体阻断剂等。这些药物尽管在临床使用上得到较好疗效，但药物作用机理或准确靶标尚未完全阐明，同时考虑到NLRP3炎症小体活化时并不仅仅产生IL-18、IL-1β，而且这些炎性细胞因子也可能是由其他炎症小体如NLRC4、AIM2活化后产生的，或者是通过非炎症小体介导的途径释放，另外细胞焦亡时释放的HMGB1等也可能参与NLRP3炎症小体相关炎症性疾病的发生发展过程，所以单纯地抑制这些下游的炎性细胞因子，不仅存在脱靶效应的风险，还可能会带来免疫抑制效应等副作用。靶向NLRP3炎症小体的小分子药物研发严重滞后，几家生物技术和制药公司主要针对NLRP3抑制剂进行研发，然而目前仍然没有直接靶向NLRP3炎症小体的抗炎药物用于临床。
在探索和研制直接靶向NLRP3炎症小体的抗炎药物过程中，有研究表明MCC950是NLRP3炎症小体相关综合征(包括自身炎症性和自身免疫性疾病)的潜在治疗药物，其研究主要发现MCC950预处理的细胞在促炎情况下抑制了ASC斑点的形成，MCC950还可以减少体内IL-1β的产生，并减弱多发性硬化症的疾病模型，如实验性自身免疫性脑脊髓炎(EAE)的严重程度；此外，在CAPS小鼠模型中，经MCC950治疗可降低新生鼠的致死率，延长其寿命近20天。并在Muckle Wells综合征中表现出抑制血浆中IL-18释放的功效。在类风湿性关节炎的药物开发中MCC950曾进入II期临床试验，但由于肝毒性太大，其临床试验已被暂停。除了MCC950，CN112654350A公开了一系列用于治疗炎症性或自身免疫性障碍的NLRP3拮抗剂，但NLRP3拮抗剂目前仍处于研发阶段，而且是和抗TNFα剂组合，显然没有直接靶向NLRP3本身的药物具有优势。
5-FUMCL是一种倍半萜类化合物的衍生物，化学结构式如下：
目前关于5-FUMCL作为一种直接靶向NLRP3炎症小体的抗炎药物的药理研究未见报道。
发明内容
本发明的目的在于提供一种特异性靶向NLRP3炎症小体抑制剂的用途。
为达到上述目的，本发明采用了以下技术方案：
5-FUMCL及其药学上可接受的盐、立体异构体、前体化合物中的任意一种或多种在制备直接靶向NLRP3炎症小体的抗炎药物中的用途。
作为优选方案，所述药物用于预防或治疗NLRP3炎症小体异常激活相关炎症性疾病。
作为优选方案，所述NLRP3炎症小体异常激活相关炎症性疾病为遗传性NLRP3依赖的自发炎症性疾病、NLRP3引起的代谢性疾病、晶体和蛋白质聚集引起的疾病、急性组织损伤、慢性炎症中的任意一种。
作为优选方案，所述NLRP3炎症小体异常激活相关炎症性疾病为Cryopyrin相关周期性综合征(CAPS)、家族性寒冷型自身炎症综合征(FCAS)、Muckle-Wells二氏综合征(MWS)、炎症性肠病(IBD)、Ⅱ型糖尿病、肥胖、非酒精性脂肪肝炎、衰老、肿瘤、动脉粥样硬化、痛风、肾脏功能紊乱、阿尔茨海默症(AD)、帕金森综合征、脓毒血症、内毒素血症、腹膜炎、战创伤、心血管应激、心肌肥大等中的任意一种。
作为优选方案，所述药物可以抑制NLRP3炎症小体的活化和/或细胞(如巨噬细胞)焦亡。
作为优选方案，所述药物具有以下抗炎作用中的一种或多种：
(i)抑制LPS和/或MSU诱导的血清中IL-1β、IL-6和IL-18的分泌；
(ii)抑制LPS和/或MSU诱导的关节和/或腹膜液中IL-1β、IL-6和IL-18的分泌；
(iii)抑制MSU诱导的关节肿胀；
(iv)抑制MSU诱导的腹腔液中中性粒细胞数量。
作为优选方案，所述药物(主要活性成分为5-FUMCL)可以用于预防或治疗急性全身性炎症。
作为优选方案，所述药物(主要活性成分为5-FUMCL)可以用于预防或治疗急性腹膜炎。
作为优选方案，所述药物(主要活性成分为5-FUMCL)可以用于预防或治疗痛风性关节炎。
作为优选方案，所述药物(主要活性成分为5-FUMCL)可以在体内外抑制NLRP3炎症小体活化。
作为优选方案，所述药物中除了含有5-FUMCL等活性成分之外，还含有药学上可接受的载体和/或其他不影响活性成分有效性的辅料。例如，所述药物还包括改善口味的甜味剂、防止氧化的抗氧化剂、各种制剂所必要的辅料等。
作为优选方案，所述药物的剂型不限，只要是能够使活性成分有效地到达体内的剂型均可，例如为片剂、胶囊剂、颗粒剂、粉末、糖浆、溶液、悬浮液、注射剂、酊剂、缓蚀剂、口服液、注射剂气雾剂、口含剂、冲剂、丸剂、滴丸、散剂、吸入粉雾剂等常见剂型或纳米制剂等缓释剂型。
上述“药学上可接受的盐”是指5-FUMCL与药学上可接受的无机酸或有机酸所形成的盐，所述无机酸为盐酸、氢溴酸、磷酸、硝酸或硫酸；所述有机酸未甲酸、乙酸、丙酸、丁二酸、1,5-萘二磺酸、亚细亚酸、草酸、酒石酸、乳酸、水杨酸、苯甲酸、戊酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、庚二酸、己二酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、对甲苯磺酸、柠檬酸或氨基酸；所述“药学上可接受的”是指适用于人而无过度不良副反应(如毒性、刺激和变态反应)，即有合理的效益/风险比。通常采用原药(例如，5-FUMCL)进行药理实验，而为了改善原药溶解性，通常在药学上是可以将原药转化改构为盐的形式。
上述“立体异构体”是指由5-FUMCL分子中原子在空间上排列方式不同所产生的异构体，例如：顺反异构体、非对映异构体、构象异构体等。
本发明的有益效果体现在：
本发明通过药理实验揭示了5-FUMCL可以在制备用于防治NLRP3炎症小体相关疾病的药物中应用，即以5-FUMCL或其药学上可接受的盐、立体异构体等作为抗炎药物活性成分，利用其炎症阻断活性对急性全身性炎症、急性腹膜炎、痛风性关节炎等炎症相关疾病发挥显著的治疗效果，并且无毒副作用。同时药理实验还揭示了5-FUMCL为特异性靶向NLRP3炎症小体抑制剂。
进一步的，本发明通过在灌胃给药5-FUMCL后利用腹腔注射LPS(脂多糖)构建急性炎症模型，并以MCC950为阳性对照，发现5-FUMCL可以在体内抑制IL-6、IL-1β的分泌。
进一步的，本发明还发现经腹腔注射5-FUMCL后，可显著改善膝关节腔注射MSU(尿酸钠)诱导的痛风性关节炎相关症状(降低关节处的炎性细胞因子的释放和关节肿胀程度)，而对于敲除了NLRP3分子的痛风性关节炎模型并不能显示出相应的抗炎功效。
进一步的，本发明还发现经腹腔注射5-FUMCL后，可明显改善腹腔注射MSU诱导的急性腹膜炎相关症状(降低血清和腹腔中的炎性细胞因子的释放和中性粒细胞的数量)，而对于敲除了NLRP3分子的急性腹膜炎模型并不能显示出相应的抗炎功效。
进一步的，以上针对不同炎症性疾病模型的药理实验结果表明，5-FUMCL可以通过特异性靶向NLRP3炎症小体活化防治NLRP3炎症小体异常活化相关疾病，如遗传性NLRP3依赖的自发炎症性疾病、NLRP3引起的代谢性疾病、晶体和蛋白质聚集引起的疾病、急性组织损伤、慢性炎症等。
附图说明
图1为5-FUMCL改善LPS诱导全身炎症实验结果，图中：A为LPS处理7h后血清中IL-6、IL-1β的含量，B为LPS处理12h后血清中IL-6、IL-1β的含量；*P<0.05，**P<0.01，***P<0.001。
图2为5-FUMCL改善MSU诱导痛风性关节炎实验结果，图中：A为给予WT小鼠处理24h后膝关节宽度变化的差值，B为给予WT小鼠处理24h后关节培养上清中IL-1β、IL-6、IL-18的含量，C为给予NLRP3-/-小鼠处理24h后膝关节宽度变化的差值，D为给予NLRP3-/-小鼠处理24h后关节培养上清中IL-1β、IL-6、IL-18的含量；*P<0.05，**P<0.01，***P<0.001。
图3为5-FUMCL改善MSU诱导急性腹膜炎实验结果，图中：A为给予WT小鼠腹腔注射MSU 6h后血清中IL-1β、IL-6、IL-18的含量，B为给予WT小鼠腹腔注射MSU 6h后腹腔液中IL-1β、IL-6、IL-18的含量，C为给予WT小鼠腹腔注射MSU 6h后腹腔液细胞中中性粒细胞的占比；D为给予NLRP3-/-小鼠腹腔注射MSU 6h后血清中IL-1β、IL-6、IL-18的含量，E为给予NLRP3-/-小鼠腹腔注射MSU 6h后腹腔液中IL-1β、IL-6、IL-18的含量，F为给予NLRP3-/-小鼠腹腔注射MSU 6h后腹腔液细胞中中性粒细胞的占比；*P<0.05，**P<0.01，***P<0.001。
图4为5-FUMCL毒副作用实验结果。
具体实施方式
下面结合附图和实施例对本发明作进一步详细说明。所述实施例仅用于解释本发明，而非对本发明保护范围的限制。
(1)5-FUMCL改善LPS诱导全身炎症实验
a1.样品制备
将5-FUMCL用二甲基亚砜(DMSO)溶解成40mg/mL的储存溶液，灌胃前用PBS(pH7.4)稀释成0.4mg/mL工作溶液，5-FUMCL的体内实验用量为50mg/kg。MCC950用PBS(pH 7.4)配制储存溶液及工作溶液，浓度均为4mg/mL，MCC950的体内实验用量为50mg/kg。
a2.实验方法
选取6～8周、体重20g左右的C57BL/6J小鼠(n＝8或6/组)；实验组小鼠灌胃给药50mg/kg 5-FUMCL，30min后腹腔注射10mg/kg LPS(该组记为5-FUMCL+LPS)。空白对照组小鼠仅灌胃等体积PBS(该组记为control)；阴性对照组小鼠仅灌胃5-FUMCL(该组记为5-FUMCL)，模型组小鼠仅腹腔注射10mg/kg LPS(即LPS组)，阳性药物组小鼠灌胃给药50mg/kgMCC950，30min后腹腔注射10mg/kg LPS(该组记为MCC950+LPS)。
a3.炎性细胞因子测定方法(参考试剂盒说明书进行操作)及统计方法(各组实验数据之间的比较使用one-way ANOVA统计分析)
a4.实验结果
如图1所示，此部分结果表明：5-FUMCL能够降低血清中IL-6、IL-1β的含量，即5-FUMCL对LPS诱导的急性炎症模型小鼠具有保护作用。
(2)5-FUMCL改善MSU诱导痛风性关节炎实验
b1.样品制备
将5-FUMCL用二甲基亚砜(DMSO)溶解成40mg/mL的储存溶液，注射前用PBS(pH7.4)稀释成0.4mg/mL工作溶液，5-FUMCL的体内实验用量为50mg/kg。
b2.实验方法
选取6～8周、体重20g左右的C57BL/6J小鼠，即WT小鼠(n＝8或6/组)；实验组小鼠腹腔给药50mg/kg 5-FUMCL，30min后在膝关节注射0.5mg/只小鼠MSU，注射MSU 24h后，将膝关节去除，在OPTI-MEM培养基中培养1h后将培养基离心，获得关节培养上清(该组记为5-FUMCL+MSU)，空白对照组小鼠仅腹腔注射等体积PBS(该组记为control)，模型组小鼠仅膝关节注射0.5mg/只小鼠MSU(即MSU组)。
选取6～8周、体重20g左右NLRP3 KO小鼠(南模生物；利用CRISPR/Cas9技术获得Nlrp3基因敲除的杂合子小鼠，再通过配繁获得的NLRP3敲除鼠纯合子)，即NLRP3-/-小鼠(n＝6/组)；实验组小鼠腹腔给药50mg/kg 5-FUMCL，30min后在膝关节注射0.5mg/只小鼠MSU，注射MSU 24h后，将膝关节去除，在OPTI-MEM培养基中培养1h后将培养基离心，获得关节培养上清(该组记为5-FUMCL+MSU)，空白对照组小鼠仅腹腔注射等体积PBS(该组记为control)，模型组小鼠仅膝关节注射0.5mg/只小鼠MSU(即MSU组)。
b3.膝关节肿胀程度评测、炎性细胞因子测定及统计方法
膝关节肿胀程度评测中采用游标卡尺测量膝关节的最大宽度；炎性细胞因子测定参考试剂盒说明书进行操作；各组实验数据之间的比较使用one-way ANOVA统计分析。
b4.实验结果
如图2所示，此部分结果表明：5-FUMCL能够改善MSU诱导的WT小鼠关节炎性反应，且关节培养上清中IL-1β、IL-6、IL-18的含量显著降低；而在相同条件下，5-FUMCL在NLRP3-/-小鼠中的上述保护作用消失。以上结果说明5-FUMCL对MSU诱导的痛风性关节炎具有显著的抗炎作用，且该抗炎作用通过NLRP3炎症小体发挥作用。
(3)5-FUMCL改善MSU诱导急性腹膜炎实验
c1.样品制备
将5-FUMCL用二甲基亚砜(DMSO)溶解成40mg/mL的储存溶液，注射前用PBS(pH7.4)稀释成0.4mg/mL工作溶液，5-FUMCL的体内实验用量为50mg/kg。MCC950用PBS(pH 7.4)配制储存溶液及工作溶液，浓度均为4mg/mL，MCC950的体内实验用量为50mg/kg。
c2.实验方法
选取6～8周、体重20g左右的C57BL/6J小鼠，即WT小鼠(n＝8或6/组)；实验组小鼠腹腔给药50mg/kg 5-FUMCL，30min后腹腔注射0.5mg/只小鼠MSU(该组记为5-FUMCL+MSU)，空白对照组小鼠仅腹腔注射等体积PBS(该组记为control)，模型组小鼠仅腹腔注射0.5mg/只小鼠MSU(即MSU组)，阳性药物组小鼠腹腔给药50mg/kg MCC950，30min后腹腔注射0.5mg/只小鼠MSU(该组记为MCC950+MSU)。
选取6～8周、体重20g左右NLRP3 KO小鼠(南模生物；利用CRISPR/Cas9技术获得Nlrp3基因敲除的杂合子小鼠，再通过配繁获得的NLRP3敲除鼠纯合子)，即NLRP3-/-小鼠(n＝6/组)；实验组小鼠腹腔给药50mg/kg 5-FUMCL，30min后腹腔注射0.5mg/只小鼠MSU(该组记为5-FUMCL+MSU)，空白对照组小鼠仅腹腔注射等体积PBS(该组记为control)，模型组小鼠仅腹腔注射0.5mg/只小鼠MSU(即MSU组)。
c3.中性粒细胞测定、炎性细胞因子测定及统计方法
中性粒细胞采用流式细胞仪检测；炎性细胞因子测定参考试剂盒说明书进行操作；各组实验数据之间的比较使用one-way ANOVA统计分析。
c4.实验结果
如图3所示，此部分结果表明：5-FUMCL能够显著降低MSU诱导后WT小鼠血清和腹腔液中IL-1β、IL-6、IL-18的含量，该腹腔液细胞中中性粒细胞的占比明显下降；而在相同条件下，5-FUMCL在MSU诱导后NLRP3-/-小鼠中的上述保护作用消失。以上结果说明5-FUMCL对MSU诱导的急性腹膜炎具有显著的抗炎作用，且该抗炎作用通过NLRP3炎症小体发挥作用。
(4)毒副作用
小鼠每天腹腔注射50mg/kg 5-FUMCL，连续注射120天，取肝脏(Liver)和胰脏(Pancreas)HE染色，无明显的炎症细胞浸润及损伤(图4)。
(5)5-FUMCL吸入粉雾剂的制备
将20g 5-FUMCL与180g辅料(麦芽糊精:乳糖质量比7:3)混合之后，加入50％的乙醇充分溶解，所得溶液经过喷雾干燥得到粉雾剂粉末，精密称量粉雾剂粉末装入3号胶囊，每粒胶囊中的装样量为20mg。其中5-FUMCL的含量为2mg。吸入粉雾剂稳定性好，便于携带，患者用药方便，肺部药物浓度高，减少了全身性药物暴露，可以有效提高重症肺炎治疗效果。
(6)5-FUMCL片剂的制备
将10g 5-FUMCL与87.5g辅料(白糊精:乳糖质量比7:3)混合之后，加入95％的乙醇，制粒，干燥，整粒(过筛)，加入硬脂酸钠2.5g，混合均匀后压片，每片重100mg，其中5-FUMCL的含量为10mg。
(7)5-FUMCL胶囊剂的制备
将15g 5-FUMCL与135g辅料(白糊精:乳糖质量比7:3)混合之后，加入95％的乙醇，制粒，干燥，整粒(过筛)，装入胶囊中，每粒重150mg，其中5-FUMCL的含量为15mg。
(8)5-FUMCL粉针剂的制备
将1g 5-FUMCL与5g甘露醇溶解于170mL的注射用水中，初次混匀之后定容到200mL，过滤所得到的溶液，装入西林瓶中，每瓶1mL，冻干，密封、灭菌，即得到每支含有5mg5-FUMCL的注射用粉针剂。
(9)用法用量
胶囊剂，成人用量为一次2～4粒，一日3次。12岁以下儿童用量减半。
片剂，成人用量为一次3～6片，一日3次。12岁以下儿童用量减半。
注射用粉针剂，成人用量为一次1支，静脉推注、静脉滴注或肌内注射；一日3次。12岁以下儿童用量减半。
综上所述，本发明通过实验揭示了5-FUMCL对LPS诱导的急性全身性炎症、MSU诱导的痛风性关节炎和急性腹膜炎具有显著的抗炎功效；并且5-FUMCL可以特异性靶向NLRP3炎症小体。这些实验结果表明，5-FUMCL可以通过抑制NLRP3炎症小体异常激活，抑制炎性细胞因子IL-1β、IL-6和IL-18的分泌，从而在防治NLRP3炎症小体相关炎症性疾病中展现明显的临床药用价值，尤其可作为活性成分用于制备治疗全身性炎症、痛风性关节炎、腹膜炎等炎症相关疾病的抗炎药物。
Claims (10)
1.5-FUMCL或5-FUMCL在药学上可接受的盐、立体异构体、前体化合物中的任意一种或多种在制备靶向NLRP3炎症小体的抗炎药物中的用途。
2.根据权利要求1所述的用途，其特征在于：所述药物用于预防或治疗NLRP3炎症小体异常激活相关炎症性疾病。
3.根据权利要求2所述的用途，其特征在于：所述NLRP3炎症小体异常激活相关炎症性疾病为遗传性NLRP3依赖的自发炎症性疾病、NLRP3引起的代谢性疾病、晶体和蛋白质聚集引起的疾病、急性组织损伤、慢性炎症中的任意一种。
4.根据权利要求2所述的用途，其特征在于：所述NLRP3炎症小体异常激活相关炎症性疾病为Cryopyrin相关周期性综合征、家族性寒冷型自身炎症综合征、Muckle-Wells二氏综合征、炎症性肠病、Ⅱ型糖尿病、肥胖、非酒精性脂肪肝炎、衰老、肿瘤、动脉粥样硬化、痛风、肾脏功能紊乱、阿尔茨海默症、帕金森综合征、脓毒血症、内毒素血症、腹膜炎、战创伤、心血管应激或心肌肥大。
5.根据权利要求1所述的用途，其特征在于：所述药物抑制NLRP3炎症小体的活化和/或细胞焦亡。
6.根据权利要求1所述的用途，其特征在于：所述药物具有以下抗炎作用中的一种或多种：
(i)抑制血清中IL-1β、IL-6和IL-18的分泌；
(ii)抑制关节和/或腹膜液中IL-1β、IL-6和IL-18的分泌；
(iii)抑制关节肿胀；
(iv)抑制腹腔液中中性粒细胞数量。
7.5-FUMCL或5-FUMCL在药学上可接受的盐、立体异构体、前体化合物中的任意一种或多种在制备用于预防或治疗急性全身性炎症的药物中的用途。
8.5-FUMCL或5-FUMCL在药学上可接受的盐、立体异构体、前体化合物中的任意一种或多种在制备用于预防或治疗急性腹膜炎的药物中的用途。
9.5-FUMCL或5-FUMCL在药学上可接受的盐、立体异构体、前体化合物中的任意一种或多种在制备用于预防或治疗痛风性关节炎的药物中的用途。
10.5-FUMCL或5-FUMCL在药学上可接受的盐、立体异构体、前体化合物中的任意一种或多种在抑制NLRP3炎症小体活化中的用途。
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